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G Protein‐Coupled Receptors and the G Protein Family

Alfredo Ulloa‐Aguirre, P. Michael Conn

10.1002/cphy.cp070106

Source: Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology

Originally published: 1998

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Structure of G Protein‐Coupled Receptors
1.1 General Features
1.2 Ligand‐Binding Domain
1.3 G Protein‐Coupling Domain
2 The Heterotrimeric G‐Protein Family
2.1 General Features
2.2 G Protein‐Regulatory Cycle
2.3 Structural and Functional Relationships of Gα‐Subunit
2.4 Gβγ Structure and Function
3 Regulatory Mechanisms
3.1 Mechanisms that Regulate Receptor Function
3.2 G Protein‐Mediated Regulatory Mechanisms
Figure 1. Figure 1.

Putative membrane topography of G protein‐coupled receptors (GPCRs). A: Proposed seven‐transmembrane‐spanning domains of a prototypic GPCR belonging to the rhodopsin/β‐adrenergic family, showing some structural characteristics, including putative glycosylation sites (branched‐like structures) as well as some aminoacid residues involved in signal transduction, receptor phosphorylation, sequestration, and palmitoylation. The structure also shows the location of some spontaneously occurring mutations leading to constitutive activation of the receptor (for example, thyrotropin, melanocyte‐stimulating hormone, luteinizing hormone, rhodopsin, and adrenergic receptors) 250, 263, 281, 370, 398, 409, 427, 492. A region in the NH2‐terminal end of the first intracellular loop (li) involved in effector activation by the human calcitonin receptor also is shown 355. Inset: Proposed arrangement for the transmembrane helices of the β2‐adrenergic receptor, depicting the binding site for epinephrine. Note the proximity between helices 2 and 7, which is characteristic of this family of GPCRs. B, C, D: Putative membrane topographies of the rat gonadotropin‐releasing hormone receptor 232, the β‐adrenergic receptor 363, and the luteinizing hormone/choriogonadotropin receptor 421, respectively, showing some particular structure‐function relationships (11, 542, 21, 33, 153, 175, 176, 193, 405, 420, 421, 473, 545, 538,539,540). PKA, protein kinase A; PKC, protein kinase C.

[Reproduced from Ostrowski et al. 363 with permission].
Figure 2. Figure 2.

Pharmacophore map of the catecholamine‐binding site of the β‐adrenergic receptor. A catecholamine ligand is shown in a hypothetical binding site intercalated among the transmembrane helices of the receptor. Each of the large semicircles represents a transmembrane helix of the receptor, inscribed with the type of binding interaction expected. Other G protein‐coupled receptors expected to have similar interactions with their specific ligands are designated in boxes next to each helix. αAR, α‐adrenergic receptor; βAR, β‐adrenergic receptor; DAR, dopaminergic receptor; MAR, muscarinic acetylcholine receptor; 5HT‐R, 5‐hydroxytryptamine (serotonin) receptor. Inset: Model for the ligandbinding site of the β‐adrenergic receptor showing key interactions with the agonist isoproterenol.

[Reproduced from Strader et al. 450, 454 with permission.]
Figure 3. Figure 3.

Sequence relationships between mammalian Gα‐subunits and family groupings.

[Reproduced from Hepler and Gilman 184 and Simon et al. 430 with permission.]
Figure 4. Figure 4.

Basic regulatory cycle of a G protein involving both GTP‐induced activation and subunit dissociation and GTPase‐dependent inactivation and subunit reassociation. The unoccupied receptor (Ri) interacts with a specific agonist (A), leading to activation of the receptor (Ra), which interacts with the trimeric Gαβγ protein complex, promoting Mg2+ ‐dependent GDP→GTP exchange and subunit dissociation, allowing their interaction with effectors (Ei). GAPs, GTPase‐activating proteins; ℗, phosphorylated receptor; Ea, activated effector.
Figure 5. Figure 5.

Crystal structure of Gαt‐GDP. Secondary structure labels for the GTPase domain were derived from the numerical designations used to describe the homologous ras p21 domains. Additional unique helices in Gαt, are labeled A‐G. Locations of inserts, linkers, and switch regions also are labeled 354.

[Reproduced from Rens‐Domiano and Hamm 399 with permission.]
Figure 6. Figure 6.

Ras‐dependent (right) and ‐independent (left) pathways of mitogen‐activated protein kinase (MAPK) activation by G protein‐coupled receptors [for example, α1B‐adrenergic receptor (α1B AR) and muscarinic M1‐acetylcholine receptor (M1AChR)] coupled to pertussis toxin‐insensitive (Gαq) G proteins. Gαq activates phospholipase Cβ1 (PLCβ1), resulting in the conversion of phosphatidylinositol‐4,5‐biphosphate to inositol‐1,4,5‐triphosphate (IP3) and diacylglycerol (DAG), which in turn contributes to the activation of protein kinase C (PKC), which then activates Raf kinase by a still poorly understood mechanism. Activated Gαq also interacts with other intracellular signaling molecules [PKC, protein tyrosine kinases (PTK), etc.] to activate the Ras‐regulated MAPK cascade. MEK, mitogen‐activated/extracellular signal‐regulated kinase.


Figure 1.

Putative membrane topography of G protein‐coupled receptors (GPCRs). A: Proposed seven‐transmembrane‐spanning domains of a prototypic GPCR belonging to the rhodopsin/β‐adrenergic family, showing some structural characteristics, including putative glycosylation sites (branched‐like structures) as well as some aminoacid residues involved in signal transduction, receptor phosphorylation, sequestration, and palmitoylation. The structure also shows the location of some spontaneously occurring mutations leading to constitutive activation of the receptor (for example, thyrotropin, melanocyte‐stimulating hormone, luteinizing hormone, rhodopsin, and adrenergic receptors) 250, 263, 281, 370, 398, 409, 427, 492. A region in the NH2‐terminal end of the first intracellular loop (li) involved in effector activation by the human calcitonin receptor also is shown 355. Inset: Proposed arrangement for the transmembrane helices of the β2‐adrenergic receptor, depicting the binding site for epinephrine. Note the proximity between helices 2 and 7, which is characteristic of this family of GPCRs. B, C, D: Putative membrane topographies of the rat gonadotropin‐releasing hormone receptor 232, the β‐adrenergic receptor 363, and the luteinizing hormone/choriogonadotropin receptor 421, respectively, showing some particular structure‐function relationships (11, 542, 21, 33, 153, 175, 176, 193, 405, 420, 421, 473, 545, 538,539,540). PKA, protein kinase A; PKC, protein kinase C.

[Reproduced from Ostrowski et al. 363 with permission].


Figure 2.

Pharmacophore map of the catecholamine‐binding site of the β‐adrenergic receptor. A catecholamine ligand is shown in a hypothetical binding site intercalated among the transmembrane helices of the receptor. Each of the large semicircles represents a transmembrane helix of the receptor, inscribed with the type of binding interaction expected. Other G protein‐coupled receptors expected to have similar interactions with their specific ligands are designated in boxes next to each helix. αAR, α‐adrenergic receptor; βAR, β‐adrenergic receptor; DAR, dopaminergic receptor; MAR, muscarinic acetylcholine receptor; 5HT‐R, 5‐hydroxytryptamine (serotonin) receptor. Inset: Model for the ligandbinding site of the β‐adrenergic receptor showing key interactions with the agonist isoproterenol.

[Reproduced from Strader et al. 450, 454 with permission.]


Figure 3.

Sequence relationships between mammalian Gα‐subunits and family groupings.

[Reproduced from Hepler and Gilman 184 and Simon et al. 430 with permission.]


Figure 4.

Basic regulatory cycle of a G protein involving both GTP‐induced activation and subunit dissociation and GTPase‐dependent inactivation and subunit reassociation. The unoccupied receptor (Ri) interacts with a specific agonist (A), leading to activation of the receptor (Ra), which interacts with the trimeric Gαβγ protein complex, promoting Mg2+ ‐dependent GDP→GTP exchange and subunit dissociation, allowing their interaction with effectors (Ei). GAPs, GTPase‐activating proteins; ℗, phosphorylated receptor; Ea, activated effector.



Figure 5.

Crystal structure of Gαt‐GDP. Secondary structure labels for the GTPase domain were derived from the numerical designations used to describe the homologous ras p21 domains. Additional unique helices in Gαt, are labeled A‐G. Locations of inserts, linkers, and switch regions also are labeled 354.

[Reproduced from Rens‐Domiano and Hamm 399 with permission.]


Figure 6.

Ras‐dependent (right) and ‐independent (left) pathways of mitogen‐activated protein kinase (MAPK) activation by G protein‐coupled receptors [for example, α1B‐adrenergic receptor (α1B AR) and muscarinic M1‐acetylcholine receptor (M1AChR)] coupled to pertussis toxin‐insensitive (Gαq) G proteins. Gαq activates phospholipase Cβ1 (PLCβ1), resulting in the conversion of phosphatidylinositol‐4,5‐biphosphate to inositol‐1,4,5‐triphosphate (IP3) and diacylglycerol (DAG), which in turn contributes to the activation of protein kinase C (PKC), which then activates Raf kinase by a still poorly understood mechanism. Activated Gαq also interacts with other intracellular signaling molecules [PKC, protein tyrosine kinases (PTK), etc.] to activate the Ras‐regulated MAPK cascade. MEK, mitogen‐activated/extracellular signal‐regulated kinase.

References
 1. Aatsinki, J. T., E. M. Pietilä, J. T. Lakkakorpi, and H. J. Rajaniemi. Expression of the LH/CG receptor gene in rat ovarian tissue is regulated by an extensive alternative splicing of the primary transcript. Mol. Cell. Endocrinol. 84: 127–135, 1992.
 2. Abood, M. E., J. B. Hurley, M.‐C. Pappone, H. R. Bourne, and L. Stryer. Functional homology between signal‐coupling proteins. Cholera toxin inactivates the GTPase activity of transducin. J. Biol. Chem. 257: 10540–10543, 1982.
 3. Abou‐Samra, A. B., H. Jüppner, T. Force, M. W. Freeman, X. F. Kong, E. Schipani, P. Urena, J. Richards, J. V. Bonventre, J. T. Potts, Jr., H. M. Kronenberg, and G. V. Segre. Expression cloning of a parathyroid hormone/parathyroid hormone‐related peptide receptor from rat osteoblast‐like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol triphosphates and increases intracellular free calcium. Proc. Natl. Acad. Sci. U.S.A. 89: 2732–2736, 1992.
 4. Adie, E. J., and G. Milligan. Agonist regulation of cellular levels of the stimulatory guanine nucleotide‐binding protein, Gs, in wild‐type transfected neuroblastoma‐glioma hybrid NG108–15 cells. Biochem. Soc. Trans. 21: 432–435, 1993.
 5. Akamizu, T., D. Inoue, S. Kosugi, T. Ban, L. D. Khon, H. Imura, and T. Mori. Chimeric studies of the extracellular domain of the rat thyrotropin (TSH) receptor: aminoacids (268–304) in the TSH receptor are involved in ligand high affinity binding, but not in TSH receptor‐specific signal transduction. Endocr. J. 40: 363–372, 1993.
 6. Alblas, J., E. J. Van Corven, P. L. Hordijk, G. Milligan, and W. H. Moolenaar. Gi‐mediated activation of the p21ras‐mitogen‐activated protein kinase pathway by α2‐adrenergic receptors expressed in fibroblasts. J. Biol. Chem. 268: 22235–22238, 1993.
 7. Amatruda, T. T. I., D. A. Steele, V. Z. Slepak, and M. I. Simon. Gα16, a G protein α subunit specifically expressed in hematopoietic cells. Proc. Natl. Acad. Sci. U.S.A. 88: 5587–5591, 1991.
 8. Arshavsky, V. Y., and M. D. Bownds. Regulation of deactivation of photoreceptor G protein by its target enzyme and cGMP. Nature 357: 416–417, 1992.
 9. Arshavsky, V. Y., M. P. Gray‐Keller, and M. D. Bownds. cGMP suppresses GTPase activity of a portion of transducin equimolar to phosphodiesterase in frog rod outer segments. Light‐induced cGMP decreases as a putative feedback. J. Biol. Chem. 266: 18530–18537, 1991.
 10. Ashkenazy, A., E. G. Peralta, J. W. Winslow, J. Ramachandran, and D. J. Capon. Functional diversity of muscarinic receptor subtypes in cellular signal transduction and growth. Trends Pharmacol. Sci. (Suppl.) 16–21, 1989.
 11. Awara, W. M., C.‐H. Guo, and P. M. Conn. Effects of Asn318 and Asp87 Asn318 mutations on signal transduction by the gonadotropin‐releasing hormone receptor and receptor regulation. Endocrinology 137: 655–662, 1996.
 12. Baldwin, J. M. The probable arrangement of the helices in G protein‐coupled receptors. EMBO J. 12: 1693–1703, 1993.
 13. Baldwin, J. M. Structure and function of receptors coupled to G proteins. Curr. Opin. Cell Biol. 6: 180–190, 1994.
 14. Barak, L. S., M. Tiberi, N. J. Freedman, M. M. Kwatra, R. J. Lefkowitz, and M. G. Caron. A highly conserved tyrosine residue in G protein‐coupled receptors is required for agonistmediated β2‐adrenergic receptor sequestration. J. Biol. Chem. 269: 2790–2795, 1994.
 15. Bauer, P. H., S. Müller, M. Puzicha, S. Pippig, B. Obermaier, E. J. M. Helmreich, and M. J. Lohse. Phosducin is a protein kinase A‐regulated G‐protein regulator. Nature 358: 73–76, 1992.
 16. Beals, C. R., C. B. Wilson, and R. M. Perlmutter. A small multigene family encodes Gi signal transduction. Proc. Natl. Acad. Sci. U.S.A. 84: 7886–7889, 1987.
 17. Benovic, J. L., M. Bouvier, M. G. Caron, and R. J. Lefkowitz. Regulation of adenylyl cyclase‐coupled β‐adrenergic receptors. Annu. Rev. Cell Biol. 4: 405–428, 1988.
 18. Benovic, J. L., C. Staniszewski, R. A Cerione, J. Codina, R. J. Lefkowitz, and M. G. Caron. The mammalian β‐adrenergic receptor: structural and functional characterization of the carbohydrate moiety. J. Recep Res. 7: 257–281, 1987.
 19. Berlot C. H., and H. R. Bourne. Identification of effector‐activating residues of Gsa. Cell 68: 911–922, 1992.
 20. Berstein, G., J. L. Blank, D.‐Y. Jhon, J. H. Exton, S. G. Rhee, and E. M. Ross. Phospholipase Cβ1 is a GTPase‐activating protein for Gq/11, its physiological regulator. Cell 70: 411–418, 1992.
 21. Berstein, G., J. L. Blank, A. V. Smrcka, T. Higashijima, P. C. Sternweis, J. H. Exton, and E. M. Ross. Reconstitution of agonist‐stimulated phosphatidylinositol 4,5‐biphosphate hydrolysis using purified m1 muscarinic receptor, Gq/11, and phospholipase Cβ1. J. Biol. Chem. 267: 8081–8088, 1992.
 22. Bhowmick, N., J. Huang, D. Puett, N. W. Isaacs, and A. J. Lapthorn. Determination of residues important in hormone binding to the extracellular domain of the luteinizing hormone/ choriogonadotropin receptor by site‐directed mutagenesis and modeling. Mol. Endocrinol. 10: 1147–1159, 1996.
 23. Bihoreau, C., C. Monnot, E. Davies, B. Teutsch, K. E. Berstein, P. Corvol, and E. Clauser. Mutation of Asp74 of the rat angiotensin II receptor confers changes in antagonist affinities and abolishes G‐protein coupling. Proc. Natl. Acad. Sci. U.S.A. 90: 5133–5137, 1993.
 24. Birdsall, N. J. M., F. Cohen, S. Lazareno, and H. Matsui. Allosteric regulation of G‐protein‐linked receptors. Biochem. Soc. Trans. 23: 108–111, 1995.
 25. Birnbaumer, L. Which G protein subunits are the active mediators in signal transduction? Trends Pharmacol. Sci. 8: 209–211, 1987.
 26. Birnbaumer L. G proteins in signal transduction. Annu. Rev. Pharmacol. Toxicol. 30: 675–705, 1990.
 27. Birnbaumer, L., J. Abramowitz, and A. M. Brown. Receptor‐effector coupling by G proteins. Biochim. Biophys. Acta 1031: 163–224, 1990.
 28. Birnbaumer, L., and M. Birnbaumer. Signal transduction by G proteins: 1994 edition. J. Recept. Signal Transduction Res. 15: 213–252, 1995.
 29. Blank, J. L., K. A. Brattain, and J. H. Exton. Activation of cytosolic phosphoinositide phospholipase C by G‐protein βγ subunits. J. Biol. Chem. 267: 23069–23075, 1992.
 30. Boege, F., M. Ward, R. Jurss, M. Hekman, and E. J. M. Helmreich. Role of glycosylation for β2‐adrenoceptor function in A431 cells. J. Biol. Chem. 263: 9040–9049, 1988.
 31. Bokoch, G. M. Interplay between Ras‐related and heterotrimeric GTP binding proteins: lifestyles of the BIG and little. FASEB J. 10: 1290–1295, 1996.
 32. Bourne, H. R., D. A. Sanders, and F. McCormick. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348: 125–132, 1990.
 33. Bourne, H. R., D. A. Sanders, and F. McCormick. The GTPase superfamily: conserved structure and molecular mechanism. Nature 349: 117–127, 1990.
 34. Bouvier, M., W. P. Hausdorff, A. De Blasi, B. F. O'Dowd, B. K. Kobilka, M. G. Caron, and R. J. Lefkowitz. Removal of phosphorylation sites from the β2‐adrenergic receptor delays onset of agonist‐promoted desensitization. Nature 333: 370–373, 1988.
 35. Bouvier, M., T. P. Loisel, and T. H. Hebert. Dynamic regulation of G‐protein coupled receptor palmitoylation: potential role in receptor function. Biochem. Soc. Trans. 23: 577–581, 1995.
 36. Bownds, D., J. Dawes, J. Miller, and M. Sthalman. Phosphorylation of frog photoreceptor membranes induced by light. Nature 237: 125–127, 1972.
 37. Boyer, J. L., G. L. Waldo, and T. K. Harden. βγ‐Subunit activation of G‐protein‐regulated phospholipase C. J. Biol. Chem. 267: 25451–25456, 1992.
 38. Brandt, D. R., and E. M. Ross. GTPase activity of the stimulatory GTP‐binding regulatory protein of adenylate cyclase, Gs. Accumulation and turnover of enzyme‐nucleotide intermediates. J. Biol. Chem. 260: 266–272, 1985.
 39. Bray, P., A. Carter, V. Guo, C. Puckett, J. Kamholz, A. Spiegel, and M. Nirenberg. Human cDNA clones for an α subunit of Gi signal‐transduction protein. Proc. Natl. Acad. Sci. U.S.A. 84: 5115–5119, 1987.
 40. Bray, P., A. Carter, C. Simons, V. Guo, C. Puckett, J. Kamholz, A. Spiegel, and M. Nirenberg. Human cDNA clones for four species of Gαs signal transduction protein. Proc. Natl. Acad. Sci. U.S.A. 83: 8893–8897, 1986.
 41. Breitwieser, G. E., and G. Szabo. Uncoupling of cardiac muscarinic and β‐adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature 317: 538–540, 1985.
 42. Breitwieser, G. E., and G. Szabo. Mechanism of muscarinic receptor‐induced K+ channel activation as revealed by hydrolysis‐resistant GTP analogues. J. Gen. Physiol. 91: 469–493, 1988.
 43. Brown, E. M., G. Gamba, D. Riccardi, M. Lombardi, R. Butters, O. Kifor, A. Sun, M. A. Hediger, J. Lytton, and S. C. Hebert. Cloning and characterization of an extracellular Ca2+‐sensing receptor from bovine parathyroid. Nature 366: 575–580, 1993.
 44. Bubis, J., and H. C. Khorana. Sites of interaction in the complex between β‐ and γ‐subunits of transducin. J. Biol. Chem. 265: 12995–12999, 1990.
 45. Buck, L. B. The olfatory multigene family. Curr. Opin. Neurobiol. 2: 282–288, 1992.
 46. Burgen, A. S. V. Some considerations of receptor specificity. Trends Pharmacol. Sci. (Suppl.) 1–3, 1989.
 47. Campbell, P. T., M. Hnatowich, B. F. O'Dowd, M. G. Caron, R. J. Lefkowitz, and W. P. Hausdorff. Mutations of the human β2‐adrenergic receptor that impair coupling to Gs interfere with receptor down‐regulation but not sequestration. Mol. Pharmacol. 39: 192–198, 1991.
 48. Camps, M., C. Hou, D. Sidiropoulus, J. B. Stock, K. H. Jakobs, and P. Gierschik. Stimulation of phospholipase C by guanine‐nucleotide‐binding protein βγ subunits. Eur. J. Biochem. 206: 821–831, 1992.
 49. Camps, M. C., A. Carozzi, P. Schnabel, P. Scheer, P. J. Parker, and P. Gierschik. Isoenzyme selective stimulation of phospholipase C‐β2 by G protein βγ subunits. Nature 360: 684–686, 1992.
 50. Carrasco, M. A., J. Sierralta, and P. DeMazancourt. Characterization and subcellular distribution of G‐proteins in highly purified skeletal muscle fractions from rabbit and frog. Arch. Biochem. Biophys. 310: 76–81, 1994.
 51. Cascieri, M. A., T. Ming Gong, and C. D. Strader. Molecular characterization of a common binding site for small molecules within the transmembrane domain of G‐protein coupled receptors. J. Pharmacol. Toxicol. Methods 33: 179–185, 1995.
 52. Casey, P. J. Lipid modifications of G proteins. Curr. Opin. Cell Biol. 6: 219–225, 1994.
 53. Casey, P. J., H. K. W. Fong, M. I. Simon, and A. G. Gilman. Gz, a guanine nucleotide‐binding protein with unique biochemical properties. J. Biol. Chem. 265: 2383–2390, 1990.
 54. Cassel, D., and Z. Selinger. Mechanism of adenylate cyclase activation by cholera toxin. Inhibition of GTP hydrolysis at the regulatory site. Proc. Natl. Acad. Sci. U.S.A. 74: 3307–3311, 1977.
 55. Chattopadhyay, N., A. Mithal, and E. M. Brown. The calcium‐sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. Endocr. Rev. 17: 289–307, 1996.
 56. Chen, C. K., J. Inglese, R. J. Lefkowitz, and J. B. Hurley. Ca2+‐dependent interaction of recoverin with rhodopsin. J. Biol. Chem. 270: 18060–18066, 1995.
 57. Chen, J. Q., and R. Iyengar. Inhibition of cloned adenylyl cyclases by mutant‐activated Giα and specific suppression of type‐2 adenylyl cyclase inhibition by phorbol ester treatment. J. Biol. Chem. 268: 12253–12256, 1993.
 58. Chen, R., K. A. Lewis, M. H. Perrin, and W. W. Vale. Expression cloning of a human corticotropin‐releasing‐factor receptor. Proc. Natl. Acad. Sci. U.S.A. 90: 8967–8971, 1993.
 59. Chen, Y., D. Gral, A. E. Salcini, P. G. Pelicci, J. Pouyssegur, and E. Van Obberghen‐Schilling. Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein‐coupled thrombin receptor. EMBO J. 15: 1037–1044, 1996.
 60. Cheung, A. H., R. R. Huang, M. P. Graziano, and C. D. Strader. Specific activation of Gs by synthetic peptides corresponding to an intracellular loop of the β‐adrenergic receptor. FEBS Lett. 279: 277–280, 1991.
 61. Cheung, A. H., R. R. Huang, and C. D. Strader. Involvement of specific hydrophobic, but not hydrophilic amino acids in the third intracellular loop of the β‐adrenergic receptor in the activation of Gs. Mol. Pharmacol. 41: 1061–1065, 1992.
 62. Chung, F.‐Z., C.‐D. Wang, P. C. Potter, J. C. Venter, and C. M. Fraser. Site‐directed mutagenesis and continuous expression of human β3‐adrenergic receptors. J. Biol. Chem. 263: 4052–4055, 1988.
 63. Clapham, D. E., and E. J. Neer. New roles for G‐protein βγ‐dimers in transmembrane signalling. Nature 365: 403–406, 1993.
 64. Clark, R. B., J. Friedman, R. A. Dixon, and C. D. Strader. Identification of a specific site required for rapid heterologous desensitization of the β‐adrenergic receptor by cAMP‐dependent protein kinase. Mol. Pharmacol. 36: 343–348, 1989.
 65. Clarke, S. Protein isoprenylation and methylation at carboxyterminal cysteine residues. Annu. Rev. Biochem. 61: 355–386, 1992,.
 66. Cobb, M. H., and E. J. Goldsmith. How MAP kinases are regulated. J. Biol. Chem. 270: 14843–14846, 1995.
 67. Coleman, D. E., A. M. Berghuis, E. Lee, M. E. Linder, A. G. Gilman, and S. R. Sprang. Structures of active conformations of Giα1 and the mechanism of GTP hydrolysis. Science 265: 1405–1412, 1994.
 68. Conklin, B. R., and H. R. Bourne. Structural elements of Gα subunits that interact with Gβγ, receptors and effectors. Cell 73: 631–641, 1993.
 69. Conn, P. M., D. C. Rogers, and S. G. Seay. Biphasic regulation of the gonadotropin‐releasing hormone receptor by receptor microaggregation and intracelullar Ca2+ levels. Mol. Pharmacol. 25: 51–55, 1984.
 70. Cook, S. J., and F. McCormick. Inhibition by cAMP of Rasdependent activation of Raf. Science 262: 1069–1072, 1993.
 71. Coso, O. A., M. Chiariello, G. Kalinec, L. M. Kyriakis, J. Woodgett, and J. S. Gutkind. Transforming G protein‐coupled receptors potently activate JNK (SAPK). Evidence for a divergence from the tyrosine kinase signaling pathway. J. Biol. Chem. 270: 5620–5624, 1995.
 72. Coso, O. A., M. Chiariello, J. C. Yu, H. Teramoto, P. Crespo, N. Xu, T. Miki, and J. S. Gutkind. The small GTP binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81: 1137–1146, 1995.
 73. Costa, T., Y. Ogino, P. J. Munson, H. O. Onaran, and D. Rodbard. Drug efficacy at guanine nucleotide‐binding regulatory protein‐linked receptors: thermodynamic interpretation of negative antagonism and of receptor activity in the absence of ligand. Mol. Pharmacol. 41: 549–560, 1992.
 74. Cotecchia, S., S. Exum, M. G. Caron, and R. J. Lefkowitz. Regions of the α1‐adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. Proc. Natl. Acad. Sci. U.S.A. 87: 2896–2900, 1990.
 75. Cotecchia, S., J. Ostrowski, M. A. Kjelsberg, M. G. Caron, and R. J. Lefkowitz. Discrete amino acid sequences of the α1‐adrenergic receptor determine the selectivity of coupling to phosphatidylinositol hydrolysis. J. Biol. Chem. 267: 1633–1639, 1992.
 76. Coughlin, S. R. Expanding horizons for receptors coupled to G proteins: diversity and disease. Curr. Opin. Cell Biol. 6: 191–197, 1994.
 77. Crespo, P., T. G. Cachero, N. Xu, and J. S. Gutkind. Dual effect of β‐adrenergic receptors on mitogen‐activated protein kinase. Evidence for a βγ‐dependent activation and a Gαs‐cAMP‐mediated inhibition. J. Biol. Chem. 270: 25259–25265, 1995.
 78. Crespo, P., W. F. Simonds, and J. S. Gutkind. Ras‐dependent activation of MAP kinase pathway mediated by G‐protein βγ subunits. Nature 369: 418–420, 1994.
 79. Curtis C. A. M., M. Wheatley, S. Bansal, N. J. Birdsall, P. Eveleigh, E. K. Pedder, D. Poyner, and E. C. Hulme. Propylben‐zilylcholine mustard labels an acidic residue in transmembrane helix 3 of the muscarinic receptor. J. Biol. Chem. 264: 489–495, 1989.
 80. Dahl, S. G., O. Edvardsen, and I. Sylte. Molecular dynamics of dopamine at the D2 receptor. Proc. Natl. Acad. Sci. U.S.A. 88: 8111–8115, 1991.
 81. Damaj, B. B., S. R. McColl, K. Neote, N. Songqing, K. T. Ogborn, C. A. Hébert, and P. H. Naccache. Identification of G‐protein binding sites of the human interleukin‐8 receptors by functional mapping of the intracellular loops. FASEB J. 10: 1426–1434, 1996.
 82. Daniel‐Issakani, S., A. M. Spiegel, and B. Strulovici. Lipopolysaccharide response is linked to the GTP binding domain, Gi–2, in the promonocytic cell line U937. J. Biol. Chem. 264: 20240–20247, 1989.
 83. Davidson, J. S., C. A. Flanagan, P. D. Davies, J. Hapgood, D. Myburgh, R. Elario, R. P. Millar, W. Forrest‐Owen, and C. A. McArdle. Incorporation of an additional glycosylation site enhances expression of functional human gonadotropin‐releasing hormone receptor. Endocrine 4: 207–212, 1996.
 84. Davidson, J. S., C. A. Flanagan, W. Zhou, I. I. Becker, R. Elario, W. Emeran, S. C. Seaflon, and R. P. Millar. Identification of N‐glycosylation sites in the gonadotropin‐releasing hormone receptor: role in receptor expression but not ligand binding. Mol. Cell. Endocrinol. 107: 241–245, 1995.
 85. Davis, R. J. The mitogen‐activated protein kinase signal transduction pathway. J. Biol. Chem. 268: 14553–14556, 1993.
 86. Davis, R. J. MAPKs: new JNK expands the group. Trends Biochem. Sci. 19: 470–473, 1994.
 87. De Almeida Catanho, M.‐T. J., A. Bérault, M. Théoleyre, and M. Jutisz. Solubilization and partial purification of the high‐affinity gonadoliberin receptor from the bovine pituitary gland. Arch. Biochem. Biophys. 225: 535–542, 1983.
 88. De la Peña, P., L. M. Delgado, D. Del Camino, and F. Barros. Two isoforms of the thyrotropin‐releasing hormone receptor generated by alternative splicing have indistinguishable functional properties. J. Biol. Chem. 267: 25703–25708, 1992.
 89. De Lean, A., J. M. Stadel, and R. J. Lefkowitz. A ternary complex model explains the agonist‐specific binding properties of the adenylate cyclase‐coupled β‐adrenergic receptor. J. Biol. Chem. 255: 7108–7117, 1980.
 90. Degtyarev, M. Y., A. M. Spiegel, and T. L. Z. Jones. Increased palmitoylation of the Gs protein α subunit after activation by the β‐adrenergic receptor or cholera toxin. J. Biol. Chem. 268: 23769–23772, 1993.
 91. Degtyarev, M. Y., A. M. Spiegel, and T. L. Z. Jones. The G protein αs subunit incorporates [3H]‐palmitic acid and mutation of cysteine‐3 prevents this modification. Biochemistry 32: 8057–8061, 1993.
 92. DeMartino, J. A., G. V. Riper, S. J. Siciliano, C. J. Molineaux, Z. D. Konteatis, H. Rosen, and M. S. Springer. The amino terminus of the human C5a receptor is required for high affinity C5a binding and for receptor activation by C5a but not C5a analogs. J. Biol. Chem. 269: 14446–14450, 1994.
 93. Denhardt, D. T. Signal‐transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. Biochem J. 318: 729–747, 1996.
 94. Denker, B. M., E. J. Neer, and C. J. Schmidt. Mutagenesis of the amino terminus of the α subunit of the G protein, Go: in vitro characterization of αoβγ interactions. J. Biol. Chem. 267: 6272–6277, 1992.
 95. Derijard, B., M. Hibi, I. Wu, T. Barret, B. Su, T. Deng, M. Karin, and R. J. Davis. JNK1: a protein kinase stimulated by UV light and Ha‐Ras that binds and phosphorylates the c‐Jun activation domain. Cell 76: 1025–1037, 1994.
 96. Dever, T. E., M. J. Glynias, and W. C. Merrick. The GTP‐binding domain: three consensus sequence elements with distinct spacing. Proc. Natl. Acad. Sci. U.S.A. 84: 1814–1818, 1987.
 97. Dhanasekaran, N., and J. M. Dermott. Signaling by the G12 class of G proteins. Cell. Signal. 8: 235–245, 1996.
 98. Dhanasekaran, N., I. E. Heasley, and G. L. Johnson. G protein‐coupled receptor systems involved in cell growth and oncogenesis. Endocr. Rev. 16: 259–270, 1995.
 99. Dixon, R. A., I. S. Sigal, M. R. Candelore, R. B. Register, E. Rands, and C. D. Strader. Structural features required for ligand binding to the β‐adrenergic receptor. EMBO J. 6: 3269–3275, 1987.
 100. Dixon, R. A., I. S. Sigal, E. Rands, R. B. Register, M. R. Candelore, A. D. Blake, and S. D. Strader. Ligand binding to the β‐adrenergic receptor involves its rhodopsin‐like core. Nature 326: 73–77, 1987.
 101. Dixon, R. A. F., B. K. Kobilka, D. J. Strader, J. L. Benovic, H. G. Dohlman, T. Frielle, M. A. Bolanowsky, C. D. Bennet, E. Rands, R. E. Diehl, R. A. Mumford, E. E. Slater, I. S. Sigal, M. G. Caron, R. J. Lefkowitz, and C. D. Strader. Cloning the gene and cDNA for mammalian β‐adrenergic receptor and homology with rhodopsin. Nature 321: 75–79, 1986.
 102. Dixon, R. A. F., I. S. Sigal, M. R. Candelore, R. B. Register, W. Scattergood, E. Rands, and C. D. Strader. Structural features required for ligand binding to the β‐adrenergic receptor. EMBO J. 11: 3269–3275, 1987.
 103. Dixon, R. A. F., I. S. Sigal, and C. D. Strader. Structure‐function analysis of the β‐adrenergic receptor. Cold Spring Harb. Symp. Quant. Biol. 53: 487–497, 1988.
 104. Dohlman, H. G., M. Bouvier, J. L. Benovic, M. G. Caron, and R. J. Lefkowitz. The multiple membrane spanning topography of the β2‐adrenergic receptor. Localization of the sites of binding, glycosylation and regulatory phosphorylation by limited proteolysis. J. Biol. Chem. 262: 14282–14288, 1987.
 105. Dohlman, H. G., M. G. Caron, A. DeBlasi, T. Frielle, and R. J. Lefkowitz. Role of extracellular disulfide‐bonded cysteines in the ligand binding function of the β2‐adrenergic receptor. Biochemistry 29: 2335–2342, 1990.
 106. Dohlman, H. G., and J. Thorner. RGS proteins and signaling by hetrotrimeric G proteins. J. Biol. Chem. 272: 3871–3874, 1997.
 107. Dohlman, H. G., J. Thorner, M. G. Caron, and R. J. Lefkowitz. Model systems for the study of seven‐transmembrane‐segment receptors. Annu. Rev. Biochem. 60: 653–688, 1991.
 108. Doss, R. C., N. R. Kramarcy, T. K. Harden, and J. P. Perkins. Effects of tunicamycin on the expression of beta‐adrenergic receptors in human astrocytoma cells during growth and recovery from agonist‐induced down‐regulation. Mol. Pharmacol. 27: 507–516, 1985.
 109. Downes, C. P. G protein‐dependent regulation of phospholipase C. Trends Pharmacol. Sci. (Suppl.): 39–42, 1989.
 110. Dratz, E. D., J. E. Fursteneau, C. G. Lambert, D. L. Thireault, H. Rarick, T. Schepers, S. Pakhlevaniants, and H. E. Hamm. NMR structure of receptor‐bound G‐protein peptide. Nature 363: 276–280, 1993.
 111. Druey, K. M., K. J. Blumer, V. H. Kang, and J. H. Kehrl. Inhibition of G‐protein‐mediated MAP kinase activation by a new mammalian gene family. Nature 379: 742–746, 1996.
 112. Emorine, L. J., S. Maurullo, C. Delavier‐Klutchko, S. V. Kaveri, O. Durieu‐Trautmann, and A. D. Strosberg. Structure of the gene encoding for human β2‐adrenergic receptor: expression and promoter characterization. Proc. Natl. Acad. Sci. U.S.A. 84: 6995–6999, 1987.
 113. Esapa, C., S. Foster, S. Johnson, J. L. Jameson, P. Kendall‐Taylor, and P. E. Harris. G protein and thyrotropin receptor mutations in thyroid neoplasia. J. Clin. Endocrinol. Metab. 82: 493–496, 1997.
 114. Exton, J. H. Phosphoinositide phospholipases and G proteins in hormone action. Annu. Rev. Physiol. 56: 349–369, 1994.
 115. Exton, J. H. Regulation of phosphoinositide phospholipases by hormones, neurotransmitters, and other agonists linked to G proteins. Annu. Rev. Pharmacol. Toxicol. 36: 481–509, 1996.
 116. Fantl, W. J., D. E. Johnson, and L. T. Williams. Signaling by receptor tyrosine kinases. Annu. Rev. Biochem. 62: 453–481, 1993.
 117. Farahbakhsh, Z. T., K. Hideg, and W. L. Hubbell. Photoactivated conformational changes in rhodopsin: a time‐resolved spin label study. Science 262: 1416–1419, 1993.
 118. Fargin, A., J. R. Raymond, J. W. Regan, S. Cotecchia, R. J. Lefkowitz, and M. G. Caron. Effector coupling mechanisms of the cloned 5‐HT1A receptor. J. Biol. Chem. 264: 14848–14852, 1989.
 119. Faure, M. A., A. Voyno‐Yasenetskaya, and H. R. Bourne. cAMP and βγ subunits of heterotrimeric G proteins stimulate the mitogen‐activated protein kinase pathway in COS‐7 cells. J. Biol. Chem. 269: 7851–7854, 1994.
 120. Feder, D., M. J. Im, H. W. Klein, M. Hekman, A. Holzhofer, C. Dees, A. Levitzki, E. J. Helmreich, and T. Pfeuffer. Reconstitution of β1‐adrenoceptor‐dependent adenylate cyclase from purified components. EMBO J. 5: 1509–1514, 1986.
 121. Federman, A. D., B. R. Conklin, K. A. Schrader, R. R. Reed, and H. R. Bourne. Hormonal stimulation of adenylyl cyclase through Giprotein βγ subunits. Nature 356: 159–161, 1992.
 122. Fields, T. A., and P. J. Casey. Signalling functions and biochemical properties of pertussis toxin‐resistant G‐proteins. Biochem. J. 321: 561–571, 1997.
 123. Findlay, J. B., and D. J. Pappin. The opsin family of proteins. Biochem J. 238: 625–642, 1986.
 124. Flanagan, C. A., I. I. Becker, J. S. Davidson, I. K. Wakefield, W. Zhou, S. C. Seaflon, and R. P. Millar. Glutamate301 of the mouse gonadotrophin releasing hormone receptor determines the specificity for Arginine8 of the mammalian gonadotrophin releasing hormone. J. Biol. Chem. 269: 22636–22641, 1994.
 125. Florio, V. A., and P. C. Sternweis. Mechanisms of muscarinic receptor action on Go in reconstituted phospholipid vesicles. J. Biol. Chem. 264: 3909–3915, 1989.
 126. Fong, H. K. W., K. K. Yoshimoto, P. Eversole‐Cire, and M. I. Simon. Identification of a GTP‐binding protein α‐subunit that lacks an apparent ADP‐ribosylation site for pertussis toxin. Proc. Natl. Acad. Sci. U.S.A. 85: 3066–3070, 1988.
 127. Fong, T. M. Mechanistic hypothesis for the activation of G‐protein‐coupled receptors. Cell. Signal. 8: 217–224, 1996.
 128. Fong, T. M., S. A. Anderson, H. Yu, R.‐R. C. Huang, and C. D. Strader. Differential activation of intracellular effector by two isoforms of human neurokinin‐1 receptor. Mol. Pharmacol. 41: 24–30, 1991.
 129. Fong, T. M., R. R. Huang, and C. D. Strader. Localization of agonist and antagonist binding domains of the human neurokinin‐1 receptor. J. Biol. Chem. 267: 25664–25667, 1992.
 130. Fong, T. M., R. R. Huang, H. Yu, and C. D. Strader. Mapping the ligand binding site of the NK‐1 receptor. Regul. Pept. 46: 43–48, 1993.
 131. Fong, T. M., R. C. Huang, H. Yu, C. J. Swain, D. Underwood, M. A. Cascieri, and C. D. Strader. Mutational analysis of neurokinin receptor function. Can. J. Physiol. Pharmacol. 73: 860–865, 1995.
 132. Fong, T. M., H. Yu, R. R. C. Huang, and C. D. Strader. The extracellular domain of the neurokinin‐1 receptor is required for high‐affinity binding of peptides. Biochemistry 31: 11806–11811, 1992.
 133. Fong, T. M., H. Yu, and C. D. Strader. The extracellular domain of substance P (NK1) receptor comprises part of the ligand binding site. Biophys. J. 62: 59–60, 1992.
 134. Fowles, C., R. Sharma, and M. Akhtar. Mechanistic studies on the phosphorylation of photoexcited rhodopsin. FEBS Lett. 238: 56–60, 1988.
 135. Franke, R. R., B. Koning, T. P. Sakmar, H. G. Khorana, and K. P. Hofmann. Rhodopsin mutants that bind but fail to activate transducin. Science 250: 123–125, 1990.
 136. Franke, R. R., T. P. Sakmar, R. M. Graham, and H. G. Khorana. Structure and function of rhodopsin. Studies of the interaction between rhodopsin cytoplasmic domain and transducin. J. Biol. Chem. 267: 14757–14774, 1992.
 137. Fraser, C. M., F. Z. Chung, C. D. Wang, and J. C. Venter. Site‐directed mutagenesis of human β‐adrenergic receptors: substitution of aspartic acid‐130 by aspargine produces a receptor with high‐affinity agonist binding that is uncoupled from adenylate cyclase. Proc. Natl. Acad. Sci. U.S.A. 85: 5478–5482, 1988.
 138. Fraser, C. M., N. H. Lee, S. M. Pellegrino, and A. R. Kerlavage. Molecular properties and regulation of G‐protein‐coupled receptors. Prog. Nucleic Acid Res. Mol. Biol. 49: 113–155, 1994.
 139. Fraser, C. M., C.‐D. Wong, D. A. Robinson, J. D. Gocayne, and J. C. Venter. Site directed mutagenesis of m1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function. Mol. Pharmacol. 36: 840–847, 1990.
 140. Freedman, N. J., and R. J. Lefkowitz. Desensitization of G protein‐coupled receptors. Recent Prog. Horm. Res. 51: 319–353, 1996.
 141. Freissmuth, M., and A. G. Gilman. Mutations of Gsα designed to alter the reactivity of the protein with bacterial toxins. Substitutions at Arg187 result in loss of GTPase activity. J. Biol. Chem. 264: 21907–21914, 1989.
 142. Frodin, M., P. Peraldi, and E. Van Obberghen. Cyclic AMP activates the mitogen‐activated protein kinase cascade in PC12 cells. J. Biol. Chem. 269: 6207–6214, 1994.
 143. Fukada, Y., T. Takao, H. Ouguro, T. Yoshizawa, T. Akino, and Y. Shimonishi. Farnesylated γ subunit of photoreceptor G protein indispensable for GTP‐binding. Nature 346: 658–660, 1992.
 144. Fung, B. K. Characterization of transducin from bovine retinal rod outer segments. I. Separation and reconstitution of the subunits. J. Biol. Chem. 258: 10495–10502, 1983.
 145. Fung, B.K.‐K., and C. R. Nash. Characterization of transducin from bovine retinal rod outer segments. II. Evidence for distinct binding sites and conformational changes revealed by limited proteolysis with trypsin. J. Biol. Chem. 258: 10503–10510, 1983.
 146. Fung, B.K.‐K., and L. Stryer. Photolyzed rhodopsin catalyzes the exchange of GTP for bound GDP in retinal rod outer segments. Proc. Natl. Acad. Sci. U.S.A. 77: 2500–2504, 1980.
 147. Gallego, C., S. K. Gupta, S. Winitz, B. J. Eisfelder, and G. L. Johnson. Myristoylation of the Gαis polypeptide, a G protein α subunit, is required for its signaling and transformation functions. Proc. Natl. Acad. Sci. U.S.A. 89: 9695–9699, 1992.
 148. Gantz, I., J. DelValle, L. Wang, T. Tashiro, G. Munzert, Y.‐J. Guo, Y. Konda, and T. Yamada. Molecular basis for the interaction of histamine with the histamine H2 receptor. J. Biol. Chem. 267: 20840–20843, 1992.
 149. Gantz, I., J. M. Schaffer, J. DelValle, C. Logsdon, V. Campbell, M. Uhler, and T. Yamada. Molecular cloning of a gene encoding the histamine H2 receptor. Proc. Natl. Acad. Sci. U.S.A. 88: 429–433, 1991.
 150. Garland, A. M., E. F. Grady, M. Lovett, S. R. Vigna, M. M. Frucht, J. E. Krause, and N. W. Bunnet. Mechanisms of desensitization and resensitization of G protein‐coupled neurokinin 1 and neurokinin 2 receptors. Mol. Pharmacol. 49: 438–446, 1996.
 151. Garritsen, A., P. J. M. Van Galen, and W. F. Simonds. The N‐terminal coiled‐coil domain of β is essential for γ association: a model for G‐protein βγ subunit interaction. Proc. Natl. Acad. Sci. U.S.A. 90: 7706–7710, 1993.
 152. George, S. T., A. E. Ruoho, and C. C. Malbon. N‐Glycosylation in expression and function of β‐adrenergic receptors. J. Biol. Chem. 261: 16559–16564, 1986.
 153. Gerszten, R. E., J. Chen, M. Ishii, K. Ishii, L. Wang, T. Nanevicz, C. W. Turck, T.‐K. H. Vu, and S. R. Coughlin. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface. Nature 368: 648–651, 1994.
 154. Gether, U., J. A. Ballesteros, R. Seifert, E. Sanders‐Bush, H. Weinstein, and B. K. Kobilka. Structural instability of a constitutively active G protein‐coupled receptor. Agonist‐independent activation due to conformational flexibility. J. Biol. Chem. 272: 2587–2590, 1997.
 155. Gilchrist, R.L., K.‐S. Ryu, I. Ji, and T. H. Ji. The luteinizing hormone/chorionic gonadotropin receptor has distinct transmembrane conductors for cAMP and inositol phosphate signals. J. Biol. Chem. 271: 19283–19287, 1996.
 156. Gilman, A. F. G proteins: transducers of receptor‐generated signals. Annu. Rev. Biochem. 56: 615–649, 1987.
 157. Gocayne, J., D. A. Robinson, M. G. Fitz‐Gerald, F.‐Z. Chung, A. R. Kerlavage, K.‐W. Lentes, J. Lai, Ch.‐D. Wang, C. M. Fraser, and J. C. Venter. Primary structure of rat β‐adrenergic and muscarinic cholinergic receptors obtained by automated DNA sequencing analysis: further evidence for a multigene family. Proc. Natl. Acad. Sci. U.S.A. 84: 8296–8300, 1987.
 158. Gordon, J. I., R. J. Duronio, D. A. Rudnick, S. P. Adams, and G. W. Goke. Protein N‐myristoylation. J. Biol. Chem. 266: 8647–8650, 1991.
 159. Grady, E. F., A. M. Garland, P. D. Gamp, M. Lovett, D. G. Payan, and N. W. Bunnet. Delineation of the endocytic pathway of substance P and its seven‐transmembrane domain NK1 receptor. Mol. Biol. Cell 6: 509–524, 1995.
 160. Graves, P. N., Y. Tomer, and T. F. Davies. Cloning and sequencing of a 1.3 kb variant of human thyrotropin receptor mRNA lacking the transmembrane domain. Biochem. Biophys. Res. Commun. 187: 1135–1143, 1992.
 161. Gromoll, J., T. Guderman, and E. Nieschlag. Molecular cloning of a truncated isoform of the human follicle stimulating hormone receptor. Biochem. Biophys. Res. Commun. 188: 1077–1083, 1992.
 162. Guan, X. M., A. Amend, and C. D. Strader. Determination of structural domains for G protein coupling and ligand binding in β3‐adrenergic receptor. Mol. Pharmacol. 48: 492–498, 1995.
 163. Guo, C.‐H., J. A. Janovick, D. Kuphal, and P. M. Conn. Transient tranfection of GGH3−1′ cells [GH3 cells stably transfected with the gonadotropin‐releasing hormone (GnRH) receptor complementary deoxyribonucleic acid] with the carboxi‐terminal of β‐adrenergic receptor kinase 1 blocks prolactin release: evidence for a role of the G protein βγ‐subunit complex in GnRH signal transduction. Endocrinology 136: 3031–3036, 1995.
 164. Gupta, S., D. Campbell, B. Derijard, and R. J. Davis. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267: 389–393, 1995.
 165. Gutowski, S., A. Smrcka, L. Nowac, D. Wu, M. Simon, and P. C. Sternweis. Antibodies to the αq subfamily guanine nucleotide‐binding regulatory protein α subunits attenuate activation of phosphatidylinositol 4,5‐biphosphate hydrolysis by hormones. J. Biol. Chem. 266: 20519–20524, 1991.
 166. Hadcock, J. R., and C. C. Malbon. Down‐regulation of β‐adrenergic receptors: agonist‐induced reduction in receptor mRNA levels. Proc. Natl. Acad. Sci. U.S.A. 85: 5021–5025, 1988.
 167. Hadcock, J. R., M. Ros, and C. C. Malbon. Agonist regulation of β‐adrenergic receptor mRNA. J. Biol. Chem. 264: 13956–13961, 1989.
 168. Hadcock, J. R., H.‐Y. Wang, and C. C. Malbon. Agonistinduced desestabilization of β‐adrenergic receptor mRNA. Attenuation of glucocorticoid‐induced up‐regulation of β‐adrenergic receptors. J. Biol. Chem. 264: 19928–19933, 1989.
 169. Hall, A. Ras‐related proteins. Curr. Opin. Cell Biol. 5: 265–268, 1993.
 170. Hall, A. Small GTP‐binding proteins and the regulation of the actin cytoskeleton. Annu. Rev. Cell Biol. 10: 31–54, 1994.
 171. Halliday, K. R. Regional homology in GTP‐binding proto‐oncogene products and elongation factors. J. Cyc. Nucl. Protein Phos. Res. 9: 435–448, 1984.
 172. Hamm, H. E. Molecular interactions between the photoreceptor G‐protein and rhodopsin. Cell. Mol. Neurobiol. 11: 563–578, 1991.
 173. Hamm, H. E., D. Deretic, A. Arendt, P. A. Hargrave, B. Koenig, and K. P. Hoffman. Site of G‐protein binding to rhodopsin mapped with synthetic peptides from the α subunit. Science 241: 832–835, 1988.
 174. Harazono, A., Y. Sugimoto, A. Ichikawa, and M. Negishi. Enhancement of adenylate cyclase stimulation by prostaglandin E receptor EP3 subtype isoforms with different efficiencies. Biochem. Biophys. Res. Commun. 201: 340–345, 1994.
 175. Hargrave, P. A., J. H. McDowell, R. J. Feldman, P. H. Atkinson, J. K. Mohana Rao, and P. Argos. Rhodopsin's protein and carbohydrate structure: selected aspects. Vision Res. 24: 1487–1499, 1984.
 176. Harhammer, R., B. Nürnberg, C. Harteneck, D. Leopoldt, T. Exner, and G. Schultz. Distinct biochemical properties of the native members of the G12 G‐protein subfamily. Characterization of Gα12 purified from rat brain. Biochem. J. 319: 165–171, 1996.
 177. Hausdorff, W. P., M. Bouvier, B. F. O'Dowd, G. P. Irons, M. G. Caron, and R. J. Lefkowitz. Phosphorylation sites on two domains of the β2‐adrenergic receptor are involved in distinct pathways of receptor desensitization. J. Biol. Chem. 264: 12657–12665, 1989.
 178. Hausdorff, W. P., M. G. Caron, and R. J. Lefkowitz. Turning off the signal: desensitization of β‐adrenergic receptor function. FASEB J. 4: 2881–2889, 1990.
 179. Hausdorff, W. P., J. A. Pitcher, D. K. Luttrell, M. E. Linder, H. Kurose, S. J. Parsons, M. G. Caron, and R. J. Lefkowitz. Tyrosine phosphorylation of G protein α subunits by pp60c‐src. Proc. Natl. Acad. Sci. U.S.A. 89: 5720–5724, 1992.
 180. Hawes, B. E., L. M. Luttrell, S. T. Exum, and R. J. Lefkowitz. Inhibition of G protein‐coupled receptor signaling by expression of cytoplasmic domains of the receptor. J. Biol. Chem. 269: 15776–15785, 1994.
 181. Hawes, B. E., T. Van Biesen, W. J. Koch, L. M. Luttrell, and R. J. Lefkowitz. Distinct pathways of Gi‐ and Gq‐mediated mitogen‐activated protein kinase activation. J. Biol. Chem. 270: 17148–17153, 1995.
 182. Hazum, E. GnRH‐receptor of rat pituitary is a glycoprotein: differential effect of neuraminidase and lectins on agonist and antagonist binding. Mol. Cell. Endocrinol. 26: 217–222, 1982.
 183. Hazum, E., I. Schvartz, Y. Waksman, and D. Keinan. Solubilization and purification of rat pituitary gonadotropin‐releasing hormone receptor. J. Biol. Chem. 261: 13043–13048, 1986.
 184. Heckert, L. L., I. J. Daley, and M. D. Griswold. Structural organization of the follicle‐stimulating hormone receptor gene. Mol. Endocrinol. 6: 70–80, 1992.
 185. Henderson, R., J. M. Baldwin, T. A. Ceska, F. Zemlin, E. Beckmann, and K. H. Downing. Model for the structure of bacteriorhodopsin based on high‐resolution electron cryomicroscopy. J. Mol. Biol. 213: 899–929, 1990.
 186. Hepler, J. R., and A. G. Gilman. G Proteins. Trends Pharmacol. Sci. 17: 383–387, 1992.
 187. Herrero, I., M. T. Miras‐Portugal, and J. Sanchez‐Prieto. Rapid desensitization of the metabotropic glutamate receptor that facilitates glutamate release in rat cerebrocortical nerve terminals. Eur. J. Neurosci. 6: 115–120, 1994.
 188. Hershey, A. D., and J. E. Krause. Molecular characterization of a functional cDNA encoding the rat substance P receptor. Science 247: 958–962, 1990.
 189. Hescheler, J., W. Rosenthal, W. Trautwein, and G. Schultz. The GTP‐binding protein, Go, regulates neuronal calcium channels. Nature 325: 445–447, 1987.
 190. Higashijima, T., J. Burnier, and E. M. Ross. Regulation of Gi, and Go by Mastoparan, related amphiphilic peptides and hydrophobic amines. J. Biol. Chem. 265: 14176–14186, 1990.
 191. Higashijima, T., K. M. Ferguson, P. C. Sternweis, E. M. Ross, M. D. Smigel, and A. G. Gilman. The effect of activating ligands on the intrinsic fluorescence of guanine nucleotide‐binding regulatory proteins. J. Biol. Chem. 262: 752–756, 1987.
 192. Higashijima, T., K. M. Ferguson, P. C. Sternweis, M. D. Smigel, and A. G. Gilman. Effects of M2+ and the βγ subunit complex on the interactions of guanine nucleotides with G proteins. J. Biol. Chem. 262: 762–766, 1987.
 193. Higgins, J. B., and P. J. Casey. In vitro processing of recombinant G‐protein γ subunits. J. Biol. Chem. 269: 9067–9073, 1994.
 194. Hipkin, R. W., J. Sánchez‐Yagüe, and M. Ascoli. Phosphorylation of the luteinizing hormone/choriogonadotropin receptor expressed in a stably transfected cell line. Mol. Endocrinol. 7: 823–832, 1993.
 195. Hipkin, R. W., Z. Wang, and M. Ascoli. Human chorionic gonadotropin (CG)‐ and phorbol ester‐stimulated phosphorylation of the luteinizing hormone/CG receptor maps to serines 635, 639, 649, and 652 in the C‐terminal cytoplasmic tail. Mol. Endocrinol. 9: 151–158, 1995.
 196. Hirisawa, A., K. Shibata, K. Horie, Y. Takei, K. Obika, T. Tanaka, N. Muramoto, K. Takagaki, J. Yano, and G. Tsujimoto. Cloning, functional expression and tissue distribution of human α1c‐adrenoceptor splice variants. FEBS Lett. 363: 256–260, 1995.
 197. Hirsch, B., M. Kudo, F. Naro, M. Conti, and A. J. W. Hsueh. The C‐terminal third of the human luteinizing hormone (LH) receptor is important for inositol phosphate release: analysis using chimeric human LH/follicle‐stimulating hormone receptors. Mol. Endocrinol. 10: 1127–1137, 1996.
 198. Hirsch, J. P., C. Dietzel, and J. Kurjan. The carboxyl terminus of Scg1, the Gα subunit involved in yeast mating, is implicated in interactions with the pheromone receptors. Genes Dev. 5: 467–474, 1991.
 199. Hirschman, J. E., G. S. De Zutter, W. F. Simonds, and D. D. Jenness. The Gβγ complex of the yeast pheromone response pathway. Subcellular fractionation and protein‐protein interactions. J. Biol. Chem. 272: 240–248, 1997.
 200. Ho, B. Y., A. Karchiin, T. Branchek, N. Davidson, and H. A. Lester. The role of conserved aspartate and serine residues in ligand binding and in function of the 5‐HT1A receptor: a site‐directed mutation study. FEBS Lett. 312: 259–262, 1992.
 201. Holtmann, M. H., S. Ganguli, E. M. Hadac, V. Dolu, and L. J. Miller. Multiple extracellular loop domains contribute critical determinants for agonist binding and activation of the secretin receptor. J. Biol. Chem. 271: 14944–14949, 1996.
 202. Horstman, D. A., S. Brandon, A. L. Wilson, C. A. Guyer, E. J. Cragoe, and L. E. Limbird. An aspartate conserved among G‐protein receptors confers allosteric regulation of α2‐adrenergic receptors by sodium. J. Biol. Chem. 265: 21590–21595, 1992.
 203. Houamed, K. M., J. L. Kuijper, T. L. Gilbert, B. A. Haldeman, P. J. O'Hara, E. R. Mulvihill, W. Almers, and F. S. Hagen. Cloning, expression and gene structure of a G‐protein coupled glutamate receptor from rat brain. Science 252: 1318–1321, 1991.
 204. Huang, R. R., P. P. Vicario, C. D. Strader, and T. M. Fong. Identification of residues involved in ligand binding to the neurokinin‐2 receptor. Biochemistry 34: 10048–10055, 1995.
 205. Huang, R. R., H. Yu, C. D. Strader, and T. M. Fong. Interaction of substance P with the second and seventh transmembrane domains of the neurokinin‐1 receptor. Biochemistry 33: 3007–3013, 1994.
 206. Huang, R. R., H. Yu, C. D. Strader, and T. M. Fong. Localization of the ligand binding site of the neurokinin‐1 receptor: interpretation of chimeric mutations and single‐residue substitutions. Mol. Pharmacol. 45: 690–695, 1994.
 207. Hulme, E. C., C. A. M. Curtis, M. Wheatley, A. Aitken, and A. C. Harris. Localization and structure of the muscarinic receptor ligand binding site. Trends. Pharmacol. Sci. (Suppl.): 22–25, 1989.
 208. Inglese, J., J. F. Glickman, W. Lorenz, M. G. Caron, and R. J. Lefkowitz. Isoprenylation of a protein kinase: requirement of farnesylation/α‐carboxy methylation for full enzymatic activity of rhodopsin kinase. J. Biol. Chem. 267: 1422–1425, 1992.
 209. Inglese, J., W. J. Koch, M. G. Caron, and R. J. Lefkowitz. Isoprenylation in the regulation of signal transduction by G‐protein‐coupled receptor kinases. Nature 359: 147–150, 1992.
 210. Inglese, J., W. J. Koch, K. Touhara, and R. J. Lefkowitz. Gβγ interactions with PH domains and Ras‐MAPK signaling pathways. Trends Biochem. Sci. 20: 151–156, 1995.
 211. Iñiguez‐Lluhi, J., C. Kleuss, and G. Gilman. The importance of G‐protein βγ subunits. Trends Cell. Biol. 3: 230–236, 1993.
 212. Iñiguez‐Lluhi, J. A., M. I. Simon, J. D. Robishaw, and A. G. Gilman. G‐protein βγ subunits synthesized in Sf9 cells. Functional characterization and the significance of prenylation of γ. J. Biol. Chem. 267: 23409–23417, 1992.
 213. Ishigara, T., S. Nakamura, Y. Kaziro, T. Takahashi, K. Takahashi, and S. Nagata. Molecular cloning and expression of a cDNA encoding the secretin receptor. EMBO J. 10: 1635–1641, 1991.
 214. Ishigara, T., R. Shigemoto, K. Mori, K. Takahashi, and S. Nagata. Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide. Neuron 8: 811–819, 1992.
 215. Ito, H., and A. G. Gilman. Expression and analysis of Gsa mutants with decreased ability to activate adenylyl cyclase. J. Biol. Chem. 266: 16226–16231, 1991.
 216. Itoh, H., R. Toyama, T. Kazana, T. Tsukamoto, M. Matsuoka, and Y. Kaziro. Presence of three distinct molecular species of Gi protein α subunit: structure of rat cDNAs and human genomic DNAs. J. Biol. Chem. 263: 6656–6664, 1988.
 217. Ito, H., R. T. Tung, T. Sugimoto, I. Kobayashi, K. Takahashi, T. Katada, M. Ui, and Y. Kurachi. On the mechanism of G protein βγ subunit activation of the muscarinic K+ channel in guinea pig atrial cell membrane. J. Gen. Physiol. 99: 961–983, 1992.
 218. Iyengar, R. Molecular and functional diversity of mammalian Gs‐stimulated adenylyl cyclases. FASEB J. 7: 768–775, 1993.
 219. Iyengar, R., and L. Birnbaumer. Hormone receptors modulate the regulatory component of adenylyl cyclases by reducing its requirement for Mg2+ ion and enhancing its extent of activation by guanine nucleotides. Proc. Natl. Acad. Sci. U.S.A. 79: 5179–5183, 1982.
 220. Janovick, J. A., S. P. Brothers, and P. M. Conn. GnRH agonist stimulates net loss in immunoassayable Gq/11 proteins. In: Program, 79th Annual Meeting of the Endocrine Society, Minneapolis. 1997, p. 168.
 221. Janovick, J. A., Haviv, F., T. D. Fitzpatrick, and P. M. Conn. Differential orientation of a GnRH agonist and antagonist in the pituitary GnRH action. Endocrinology 133: 942–945, 1993.
 222. Jelinek, L. J., S. Lok, G. B. Rosenberg, R. A. Smith, F. J. Grant, S. Biggs, P. A. Bensch, J. L. Kuijper, P. O. Sheppard, C. A. Sprecher, P. J. O'Hara, D. Foster, K. M. Walker, L. H. J. Chen, P. A. McKernan, and W. Kindsvogel. Expression cloning and signaling properties of the rat glucagon receptor. Science 259: 1614–1616, 1993.
 223. Jelsema, C. L., and J. Axelrod. Stimulation of phospholipase A2 activity in bovine rod outer segments by the βγ subunits of transducin and its inhibition by the α subunit. Proc. Natl. Acad. Sci. U.S.A. 84: 3623–3627, 1987.
 224. Jennes, L., W. E. Stumpf, and P. M. Conn. Receptor‐mediated binding and uptake of GnRH agonist and antagonist by pituitary cells. Peptides 5 (Suppl. 1): 215–220, 1984.
 225. Jhon, D.‐Y., H.‐H. Lee, D. Park, C.‐W. Lee, K.‐H. Lee, and O. J. Yoo. Cloning, sequencing, purification and Gq‐dependent activation of phospholipase C‐β3. J. Biol. Chem. 268: 6654–6661, 1993.
 226. Ji, I., and T. Ji. Asp383 in the second transmembrane domain of the lutropin receptor is important for high affinity hormone binding and cAMP production. J. Biol. Chem. 266: 14953–14957, 1991.
 227. Ji, I., R. G. Slaughter, and T. H. Ji. N‐linked oligosaccharides are not required for hormone binding of the lutropin receptor in a Leydig tumor cell line and rat granulosa cells. Endocrinology 127: 494–496, 1990.
 228. Jinnah, H. A., and P. M. Conn. GnRH‐stimulated LH release from rat anterior pituitary cells in culture: refractoriness and recovery. Am. J. Physiol. 249 (Endocrinol. Metab. 12): E619–E625, 1985.
 229. Johnson, P. S., C. K. Surrat, B. K. Seideleck, C. J. Blaschak, J. B. Wang, and G. R. Uhl. μ Opiate receptor: site‐directed mutagenesis produces differential effect on second messenger systems. In: Program, 24th Annual Meeting of the Society for Neuroscience, Miami, FL. 1994, p. 745.
 230. Jones, D. T., and R. R. Reed. Molecular cloning of five GTP‐binding protein cDNA species from rat olfactory neuroepithelium J. Biol. Chem. 262: 14241–14249, 1987.
 231. Jones, R. L. Z., W. F. Simonds, J. J. Merendino, M. R. Brann, and A. M. Spiegel. Myristoylation of an inhibitory GTP‐binding protein α subunit is essential for its membrane attachment. Proc. Natl. Acad. Sci. U.S.A. 87: 568–572, 1990.
 232. Jüppner H., A. B. Abou‐Amra, M. W. Freeman, X. F. Kong, E. Schipani, J. Richards, L. F. Kolakowski, Jr., J. Hock, J. T. Potts, Jr., H. M. Kronenberg, and G. V. Segre. A G protein‐linked receptor for parathyroid hormone and parathyroid hormone‐related peptide. Science 254: 1024–1026, 1991.
 233. Jüppner, H., E. Schipani, F. R. Bringhurst, I. McClure, H. T. Keutmann, J. T. Potts, H. M. Kronenberg, A. B. Abou‐Samra, G. V. Segre, and T. J. Gardella. The extracellular aminoterminal region of the parathyroid hormone (PTH)/PTH‐related peptide receptor determines the binding affinity for carboxyl‐terminal fragments of PTH‐(1–34). Endocrinology 134: 879–884, 1994.
 234. Kaiser, U. B., D. Zhao, G. R. Cardona, and W. Chin. Isolation and characterization of cDNAs encoding the rat pituitary gonadotropin‐releasing hormone receptor. Biochem. Biophys. Res. Commun. 189: 1645–1652, 1992.
 235. Karkar, S. S., L. C. Musgrove, D. C. Devor, J. C. Sellers, and J. D. Neil. Cloning, sequencing and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem. Biophys. Res. Commun. 189: 289–295, 1992.
 236. Karnik, S., K. Ridge, S. Bhattacharya, and G. H. Khorana. Palmitoylation of bovine opsin and its cystein mutants in COS cells. Proc. Natl. Acad. Sci. U.S.A. 90: 40–44, 1993.
 237. Karnik, S. S., J. P. Sakmann, H. B. Chen, and H. G. Khorana. Cysteine residues 110 and 187 are essential for the formation of correct structure in bovine rhodopsin. Proc. Natl. Acad. Sci. U.S.A. 85: 8459–8463, 1988.
 238. Katz, A., D. Wu, and M. I. Simon. Subunits βγ of heterotrimeric G protein activate β2 isoform of phospholipase C. Nature 360: 686–689, 1992.
 239. Kaupmann, K., C. Burns, D. Hoyer, K. Seuwen, and H. Lübbert. Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain. FEBS Lett. 331: 53–59, 1993.
 240. Kaupp, U. B., and K. W. Koch. Role of cGMP and Ca2+ in vertebrate photoreceptor excitation and adaptation. Annu. Rev. Physiol. 54: 153–176, 1992.
 241. Kawate, N., and K. M. Menon. Palmitoylation of luteinizing hormone/human choriogonadotropin receptors in transfected cells. J. Biol. Chem. 269: 30651–30658, 1994.
 242. Kennedy, K., V. Gigoux, Ch. Escrieut, B. Maigret, J. Martinez, L. Moroder, D. Fréhel, D. Gully, N. Vaysse, and D. Fourmy. Identification of two amino acids of the human cholecystokinin‐A receptor that interact with the N‐terminal moiety of cholecystokinin. J. Biol. Chem. 272: 2920–2926, 1997.
 243. Kennedy, M., and L. E. Limbird. Palmitoylation of the α2A‐ adrenergic receptors. J. Biol. Chem. 269: 31915–31922, 1994.
 244. Kennedy, M. E., and L. E. Limbird. Mutations of the α2A‐adrenergic receptor that eliminate detectable palmitoylation do not perturb receptor‐G‐protein coupling. J. Biol. Chem. 268: 8003–8011, 1993.
 245. Kennelly, P. J., and E. G. Krebs. Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. J. Biol. Chem. 266: 15555–15558, 1991.
 246. Khorana, H. G. Rhodopsin, photoreceptor of the rod cell. An emerging pattern for structure and function. J. Biol. Chem. 267: 1–4, 1992.
 247. Kim, D., D. L. Lewis, L. Graziadei, E. J. Neer, D. Bar‐Sagi, and D. E. Clapham. G‐protein βγ‐subunits activate the cardiac muscarinic K+ channel via phospholipase A2. Nature 337: 557–560, 1989.
 248. Kim, G.‐D., I. C. Carr, L. A. Anderson, J. Zabavnik, K. A. Eidne, and G. Milligan. The long isoform of the rat thyrotropin‐releasing hormone receptor down‐regulates Gq proteins. J. Biol. Chem. 269: 19933–19940, 1994.
 249. Kisselev, O., and N. Gautman. Specific interaction with rhodopsin is dependent on the γ subunit type in a G‐protein. J. Biol. Chem. 268: 24519–24552, 1993.
 250. Kisselev, O., A. Pronin, M. Ermolaeva, and N. Gautman. Receptor‐G protein coupling is established by a potential conformational switch in the βγ complex. Proc. Natl. Acad. Sci. U.S.A. 92: 9102–9106, 1995.
 251. Kjeldgaard, M., J. Nyborg, and B. F. C. Clark. The GTP binding motif: variations on a theme. FASEB J. 10: 1347–1368, 1996.
 252. Kjelsberg, M. A., S. Cotecchia, J. Ostrowski, M. G. Caron, and R. J. Lefkowitz. Constitutive activation of the α1B‐adrenergic receptor by all amino acid substitutions at a single site. J. Biol. Chem. 267: 1430–1433, 1992.
 253. Kleuss, C. J., C. Hescheler, W. Ewel, G. Rosenthal, G. Schultz, and B. Wittig. Assignment of G‐protein subtypes to specific receptors inducing inhibition of calcium channels. Nature 353: 43–48, 1991.
 254. Kobilka, B. K., R. A. F. Dixon, T. Frielle, H. G. Dohlman, M. A. Bolanowski, I. S. Sigal, T. L. Yang‐Feng, U. Francke, M. G. Caron, and R. J. Lefkowitz. cDNA for the human β‐adrenergic receptor: a protein with multiple membrane spanning domains and a chromosomal location shared with the PDGF receptor gene. Proc. Natl. Acad. Sci. U.S.A. 84: 46–50, 1987.
 255. Kobilka, B. K., T. S. Kobilka, K. W. Daniel, J. W. Regan, M. G. Caron, and R. J. Lefkowitz. Chimeric α2‐, β2‐adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificiy. Science 249: 1310–1316, 1988.
 256. Koch, C. A., D. Anderson, M. F. Moran, C. Ellis, and T. Pawson. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science 252: 668–674, 1991.
 257. Koch, W. J., B. E. Hawes, L. F. Allen, and R. J. Lefkowitz. Direct evidence that Gi‐coupled receptor stimulation of mitogen‐activated protein kinase is mediated by G βγ activation of p21ras. Proc. Natl. Acad. Sci. U.S.A. 91: 12706–12710, 1994.
 258. Kokame, K., Y. Fukada, T. Yoshizawa, T. Takao, and Y. Shimonishi. Lipid modification of the N‐terminus of photoreceptor G‐protein α‐subunit. Nature 359: 749–752, 1992.
 259. Kolch, W., G. Heidecker, G. Kochs, R. Hummel, H. Vahidi, H. Mischak, G. Finkenzeller, D. Marme, and U. R. Rapp. Protein kinase Cα activates RAF‐1 by direct phosphorylation. Nature 364: 249–252, 1993.
 260. Konig, B., A. Arendt, J. H. McDowell, M. Kahlert, P. A. Hargrave, and K. P. Hofmann. Three cytoplasmic loops of rhodopsin interact with transducin. Proc. Natl. Acad. Sci. U.S.A. 86: 6878–6882, 1989.
 261. Koo, Y. B., I. Ji, R. G. Slaughter, and T. H. Ji. Structure of the luteinizing hormone receptor gene and multiple exons of the coding sequence. Endocrinology 128: 2297–2308, 1991.
 262. Kosugi, S., F. Okajima, T. Ban, A. Hidaka, A. Shenker, and L. D. Kohn. Mutation of alanine 623 in the third cytoplasmic loop of the rat thyrotropin (TSH) receptor results in a loss in the phosphoinositide but not the cAMP signal induced by TSH and receptor antibodies. J. Biol. Chem. 267: 24153–24156, 1992.
 263. Krueger, K. M., Y. Daaka, J. A. Pitcher, and R. J. Lefkowitz. The role of sequestration in G protein‐coupled receptor resensitization. J. Biol. Chem. 272: 5–8, 1997.
 264. Kubo, T., H. Bujo, I. Akiba, J. Nakai, M. Mishina, and S. Numa. Location of a region of the muscarinic acetylcholine receptor involved in selective effector coupling. FEBS Lett. 241: 119–125, 1988.
 265. Kudo, M., Y. Osuga, B. K. Kobilka, and A.J.W. Hsueh. Transmembrane regions V and VI of the human luteinizing hormone receptor are required for constitutive activation by a mutation in the third intracellular loop. J. Biol. Chem. 271: 22470–22478, 1996.
 266. Kurachi, Y., H. Ito, T. Sugimoto, T. Shimizu, I. Miki, and M. Ui. Arachidonic acid metabolites as intracellular modulators of the G protein‐gated cardiac K+ channel. Nature 337: 555–557, 1989.
 267. Kurtenbach, E., C.A.M. Curtis, E. K. Pedder, A. Aitken, A.C.M. Harris, and E. C. Hulme. Muscarinic acetylcholine receptors. Peptide sequencing identifies residues involved in antagonist binding and disulfide bond formation. J. Biol. Chem. 265: 13702–13708, 1990.
 268. Lagnado, L., and D. Baylor. Signal flow in visual transduction. Neuron 8: 995–1002, 1992.
 269. Lambright, D. G., J. Sondek, A. Bohm, N. P. Skiba, H. E. Hamm, and P. B. Sigler. The 2.0 Å crystal structure of a heterotrimeric G protein. Nature 379: 311–319, 1996.
 270. Lameh, J., M. Philip, Y. K. Sharma, O. Moro, J. Ramachandran, and W. Sadee. Hm1 muscarinic cholinergic receptor internalization requires a domain in the third cytoplasmic loop. J. Biol. Chem. 267: 13406–13412, 1992.
 271. LaMorte, V. J., E. D. Kennedy, L. R. Collins, D. Goldstein, A. T. Harootunian, J. H. Brown, and J. R. Feramisco. A requirement for Ras protein function in thrombin‐stimulated mitogenesis in astrocytoma cells. J. Biol. Chem. 268: 19411–19415, 1993.
 272. Landis, C. A., S. B. Masters, A. Spada, A. M. Pace, H. R. Bourne, and L. Vallar. GTPase inhibiting mutations activate the α chain of Gs and stimulate adenylyl cyclase in human pituitary tumors. Nature 340: 692–696, 1989.
 273. Lange‐Carter, C. A., C. M. Pleiman, A. M. Gardner, K. J. Blumer, and G. L. Johnson. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260: 315–319, 1993.
 274. LaRosa, G. J., K. M. Thomas, M. E. Kaufmann, R. Mark, M. White, L. Taylor, G. Gray, D. Witt, and J. Navarro. Amino terminus of the interleukin‐8 receptor is a major determinant of receptor subtype specificity. J. Biol. Chem. 267: 25402–25406, 1992.
 275. Laue, L. L., W. Shao‐Ming, M. Kudo, C. J. Bourdony, G. B. Cutler, A. J. W. Hsueh, and W.‐Y. Chan. Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia. Mol. Endocrinol. 10: 987–997, 1996.
 276. Leberman, R., and U. Egner. Homologies in the primary structure of GTP‐binding proteins: the nucleotide binding site. EMBO J. 4: 339–341, 1984.
 277. Lechleiter, J., R. Hellmiss, K. Duerson, D. Ennulat, N. David, D. Clapham, and E. Peralta. Distinct sequence elements control the specificity of G‐protein activation by muscarinic acetylcholine receptor subtypes. EMBO J. 9: 4381–4390, 1990.
 278. Lee, C., T. Murakami, and W. F. Simonds. Identification of a discrete region of the G protein γ subunit conferring selectivity in βγ complex. J. Biol. Chem. 270: 8779–8784, 1995.
 279. Lee, C. H., A. Katz, and M. I. Simon. Multiple regions of Gα16 contribute to the specificity of activation by the C5A receptor. Mol. Pharmacol. 47: 218–223, 1995.
 280. Lee, C.‐W., D. J. Park, K.‐H. Lee, C. G. Kim, and S. G. Rhee. Purification, molecular cloning, and sequencing of phospholi‐pase C‐β4. J. Biol. Chem. 268: 21318–21327, 1993.
 281. Lee, E., R. Taussig, and A. G. Gilman. The G226A mutant of Gsa highlights the requirement for dissociation of G protein subunits. J. Biol. Chem. 267: 1212–1218, 1992.
 282. Leff, P. The two‐state model of receptor activation. Trends Pharmacol. Sci. 16: 89–97, 1995.
 283. Lefkowitz, R. J. Turned on to ill effect. Nature 365: 603–604, 1993.
 284. Lefkowitz, R. J., S. Cotecchia, P. Samama, and T. Costa. Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol. Sci. 14: 303–307, 1993.
 285. Lester, H. A. The permeation pathway of neurotransmittergated ion channels. Annu. Rev. Biophys. Biomol. Struct. 21: 267–292, 1992.
 286. Lev, S., H. Moreno, R. Martinez, P. Canoll, E. Peles, J. M. Musacchio, G. D. Plowman, B. Rudy, and J. Schlessinger. Protein tyrosine‐kinase PYK2 involved in Ca2+‐induced regulation of ion channel and MAP kinase functions. Nature 376: 737–745, 1995.
 287. Levis, M. J., and H. R. Bourne. Activation of the α subunit of Gs in intact cells alters its abundance, rate of degradation, and membrane avidity. J. Cell Biol. 119: 1297–1307, 1992.
 288. Liggett, S. B., M. G. Caron, R. J. Lefkowitz, and M. Hnatowich. Coupling of a mutated form of the human β2‐adrenergic receptor to Gi and Gs. J. Biol. Chem. 266: 4816–4821, 1991.
 289. Lin, H. Y., T. L. Harris, M. S. Flannery, A. Aruffo, E. H. Kaji, A. Gorn, L. F. Kolafowski, Jr., H. F. Lodish, and S. R. Goldring. Expression cloning of an adenylate cyclase‐coupled calcitonin receptor. Science 254: 1022–1024, 1991.
 290. Linder, M. E., P. Middleton, J. R. Hepler, R. Taussig, A. G. Gilman, and S. M. Mumby. Lipid modification of G‐proteins: α subunits are palmitoylated. Proc. Natl. Acad. Sci. U.S.A. 90: 3675–3579, 1993.
 291. Linder, M. E., I.‐H. Pang, R. J. Duronio, J. I. Gordon, P. C. Sternweis, and A. G. Gilman. Lipid modifications of G protein subunits. Myristoylation of Goα increases its affinity for βγ. J. Biol. Chem. 266: 4654–4659, 1991.
 292. Litosch, I. G‐protein inhibition of phospholipase C‐β1 in membranes: role of G‐protein βγ subunits. Biochem. J. 319: 173–178, 1996.
 293. Liu, J., N. Blin, B. R. Conklin, and J. Wess. Molecular mechanisms involved in muscarinic acetylcholine receptor‐mediated G protein activation studied by insertion mutagenesis. J. Biol. Chem. 271: 6172–6178, 1996.
 294. Liu, L.‐W., T.‐K. H. Vu, C. T. Esmon, and S. R. Coughlin. The region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity. J. Biol. Chem. 266: 16977–16980, 1991.
 295. Liu, M., and M. I. Simon. Regulation by cAMP‐dependent protein kinase of a G‐protein‐mediated phospholipase C. Nature 382: 83–87, 1996.
 296. Liu, X. B., D. Davis, and D. L. Segaloff. Disruption of potential sites for N‐linked glycosylation does not impair hormone binding to the lutropin/choriogonadotropin receptors if Asn‐173 is left intact. J. Biol. Chem. 268: 1513–1516, 1993.
 297. Logothetis, D. E., D. Kim, J. K. Northrup, E. J. Neer, and D. E. Clapham. Specificity of action of guanine nucleotide‐binding regulatory protein subunits on the cardiac muscarinic K+. Proc. Natl. Acad. Sci. U.S.A. 85: 5815–5818, 1988.
 298. Logothetis, D. E., Y. Kurachi, J. Galper, E. J. Neer, and D. E. Clapham. The βγ subunits of GTP‐binding proteins activate the muscarinic K+ channel in heart. Nature 325: 321–326, 1987.
 299. Lohse, M. J., J. L. Benovic, M. G. Caron, and R. J. Lefkowitz. β‐Arrestin: a protein that regulates β‐adrenergic receptor function. Science 248: 1547–1550, 1990.
 300. Loosfelt, H. M., M. Misrahi, M. Atger, R. Salesse, M. T. Vu Hai‐Luu Thi, A. Jolivet, A. Guiochon‐Mantel, S. Sar, B. Jalla, J. Garnier, and E. Milgrom. Cloning and sequencing of porcine LH‐hCG receptor cDNA: variants lacking transmembrane domain. Science 245: 525–528, 1989.
 301. Lounsbury, K. M., P. J. Casey, L. F. Brass, and D. R. Manning. Phosphorylation of Gz in human platelets: selectivity and site of modification. J. Biol. Chem. 266: 22051–22056, 1991.
 302. Lupas, A. N., J. M. Lupas, and J. B. Stock. Do G protein subunits associate via a three‐stranded coiled coil? FEBS Lett. 314: 105–108, 1992.
 303. Luttrell, L. M., J. Della Rocca, T. Van Biesen, D. K. Lutterll, and R. J. Lefkowitz. Gβγ subunits mediate Src‐dependent phosphorylation of the epidermal growth factor receptor. J. Biol. Chem. 272: 4637–4644, 1997.
 304. Luttrell, L. M., J. Ostrowski, S. Cotecchia, H. Kendall, and R. J. Lefkowitz. Antagonism of catecholamine receptor signaling by expression of cytoplasmic domains of the receptors. Science 259: 1453–1457, 1993.
 305. Lyons, J., C. A. Landis, G. Harsh, L. Vallar, K. Grunewald, H. Feichtinger, Q.‐Y. Suk, O. H. Clark, E. Kawasaki, and H. R. Bourne. Two G protein oncogenes in human endocrine tumors. Science 249: 655–659, 1990.
 306. Maeda, S., J. Lameh, W. G. Mallet, M. Philip, J. Ramachandran, and W. Sadee. Internalization of the Hm1 muscarinic cholinergic receptor involves the third cytoplasmic loop. FEBS Lett. 269: 386–388, 1990.
 307. Maggio, R., Z. Vogel, and J. Wess. Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular “cross‐talk” between G‐protein‐linked receptors. Proc. Natl. Acad. Sci. U.S.A. 90: 3103–3107, 1993.
 308. Mahan, L. C., A. M. Koachman, and P. A. Insel. Genetic analysis of β‐adrenergic receptor internalization and down‐regulation. Proc. Natl. Acad. Sci. U.S.A. 82: 129–133, 1985.
 309. Masu, M., Y. Tanabe, K. Tsuchida, R. Shigemoto, and S. Nakanishi. Sequence and expression of a metabotropic glutamate receptor. Nature 349: 760–765, 1991.
 310. Mattera, R., M. P. Graziano, A. Yatani, Z. Zhou, R. Graf, J. Codina, L. Birnbaumer, A. G. Gilman, and A. M. Brown. Splice variants of the α subunit of the G protein Gs activate both adenylyl cyclase and calcium channels. Science 243: 804–807, 1989.
 311. Mayo, K. E. Molecular cloning and expression of a pituitaryspecific receptor for growth hormone‐releasing hormone. Mol. Endocrinol. 6: 1734–1744, 1992.
 312. Mazzoni, M. R., and H. E. Hamm. Effect of monoclonal antibody binding on α‐βγ subunit interactions in the rod outer segment G protein, Gt. Biochemistry 28: 9873–9880, 1989.
 313. Mazzoni, M. R., J. A. Malinksi, and H. E. Hamm. Structural analysis of rod GTP‐binding protein, Gt: limited proteolytic digestion pattern of Gt with four proteases defines monoclonal antibody epitope. J. Biol. Chem. 266: 14072–14081, 1991.
 314. McArdle, C. A., and R. Countis. GnRH and PACAP action in gonadotropes. Cross‐talk between phosphoinositidase C and adenylyl cyclase mediated signaling pathways. Trends Endocrinol. Metab. 7: 168–175, 1996.
 315. McArdle, C. A., W. C. Gorospe, W. R. Huckle, and P. M. Conn. Homologous down‐regulation of gonadotropin‐releasing hormone receptors and desensitization of gonadotropes: lack of dependence on protein kinase C. Mol. Endocrinol. 1: 420–429, 1987.
 316. McArdle, C. A., G. B. Willars, R. C. Fowkes, S. R. Nahorski, J. S. Davidson, and W. Forrest‐Owen. Desensitization of gonadotropin‐releasing hormone action in αT3–1 cells due to uncoupling of inositol 1,4,5‐triphosphate generation and Ca2+ mobilization. J. Biol. Chem. 271: 23711–23717, 1966.
 317. McClue, S. J., B. M. Baron, and B. A. Harris. Activation of Gi protein by peptide of the muscarinic M2 receptor second intracellular loop. Eur. J. Pharmacol. 267: 185–193, 1994.
 318. McFarland, K. C., R. Sprengel, H. S. Phillips, M. Kohler, N. Rosemblit, K. Nikolics, D. L. Segaloff, and P. H. Seeburg. Lutropin‐choriogonadotropin receptor: an unusual member of the G protein receptor family. Science 245: 494–499, 1989.
 319. McLaughlin, S. K., P. J. McKinnon, and R. F. Margoolskee. Gustducin is a taste‐cell‐specific G protein closely related to the transducins. Nature 357: 563–569, 1992.
 320. Medema, R. H., and Bos, J. L. The role of p21ras in receptor tyrosine kinase signaling. Crit. Rev. Oncog. 4: 615–661, 1993.
 321. Medynski, D., S. K. Sullivan, D. Smith, C. VanDop, F.‐H. Chang, B. K.‐K. Fung, P. H. Seeburg, and H. R. Bourne. Amino acid sequence of the α subunit of transducin deduced from the cDNA sequence. Proc. Natl. Acad. Sci. U.S.A. 82: 4311–4315, 1985.
 322. Ménard, L., S. S. G. Ferguson, L. S. Barak, L. Bertrand, R. T. Premont, A.‐M. Colapietro, R. L. Lefkowitz, and M. G. Caron. Members of the G protein–coupled receptor kinase family that phosphorylate the β2‐adrenergic receptor facilitate sequestration. Biochemistry 35: 4155–4160, 1996.
 323. Miller, R. T., S. B. Masters, K. A. Sullivan, B. Beiderman, and H. R. Bourne. A mutation that prevents GTP‐dependent activation of the α chain of Gs. Nature 334: 712–715, 1988.
 324. Milligan, G. Agonist regulation of cellular G protein levels and distribution: mechanisms and functional implications. Trends Pharmacol. Sci. 14: 405–410. 1993.
 325. Milligan, G. Signal sorting by G‐protein‐linked receptors. Adv. Pharmacol. 32: 1–29, 1995.
 326. Milligan, G., R. A. Bond, and M. Lee. Inverse agonism: pharmacological curiosity or potential therapeutic strategy? Trends Pharmacol. Sci. 16: 10–13, 1995.
 327. Minden, A., A. Lin, F.‐X. Claret, A. Abo, and M. Karin. Selective activation of the JNK signaling cascade and c‐Jun transcriptional activity by the small GTPases Rac abd Cdc42. Cell 81: 1147–1157, 1995.
 328. Minegishi, T., K. Nakamura, Y. Takakura, K. Miyamoto, Y. Hasegawa, Y. Ibuki, and M. Igarashi. Cloning and sequencing of human LH/hCG receptor cDNA. Biochem. Biophys. Res. Commun. 172: 1049–1054, 1990.
 329. Moffett, S., B. Mouillac, H. Bonin, and M. Bouvier. Altered phosphorylation and desensitization patterns of a human β2‐adrenergic receptor lacking the palmitoylated Cys341. EMBO J. 12: 349–356, 1993.
 330. Möller, W., and R. Amons. Phosphate‐binding sequences in nucleotide‐binding proteins. FEBS Lett. 186: 1–7, 1985.
 331. Morrison, D. F., P. J. O'Brien, and D. R. Pepperberg. Depalmitoylation with hydroxylamine alters the functional properties of rhodopsin. J. Biol. Chem. 266: 20118–20123, 1991.
 332. Mouillac, B., M. Caron, H. Bonin, M. Dennis, and M. Bouvier. Agonist‐modulated palmitoylation of β2‐adrenergic receptors in sf9 cells. J. Biol. Chem. 267: 21733–21737, 1992.
 333. Moyle, W. R., M. P. Bernard, R. V. Myers, O. M. Marko, and C. D. Strader. Lutropin/β‐adrenergic receptor chimeras bind choriogonadotropin and adrenergic ligands but are not expressed at the cell surface. J. Biol. Chem. 266: 10807–10812, 1991.
 334. Mulheron, J. G., S. J. Casanas, J. M. Arthur, M. N. Garnovskaya, T. W. Gettys, and J. R. Raymond. Human 5‐HT1A receptor expressed in insect cells activates endogenous G0‐like G proteins. J. Biol. Chem. 269: 12954–12962, 1994.
 335. Mumby, S. M.P.J. Casey, A. G. Gilman, S. Gutowski, and P. C. Stemweis. G protein γ subunits contain a 20‐carbon isoprenoid. Proc. Natl. Acad. Sci. U.S.A. 87: 5873–5877, 1990.
 336. Mumby, S. M., R. O. Heukeroth, J. E. Gordon, and A. G. Gilman. G‐protein α‐subunit expression, myristoylation, and membrane association in COS cells. Proc. Natl. Acad. Sci. U.S.A. 87: 728–733, 1990.
 337. Mumby, S. M., C. Kleuss, and A. G. Gilman. Receptor regulation of G‐protein palmitoylation. Proc. Natl. Acad. Sci. U.S.A. 91: 2800–2804, 1994.
 338. Murayama, T., and M. Ui. Loss of the inhibitory function of the guanine nucleotide regulatory component of adenylate cyclase due to its ADP ribosylation by islet‐activating protein, pertussis toxin, in adipocyte membranes. J. Biol. Chem. 258: 3319–3326, 1983.
 339. Nagayama, Y., D. Russo, H. L. Wadsworth, G. D. Chazenbalk, and B. Rapoport. Eleven amino acids (Lys‐201 to Lys‐211) and 9 amino acids (Gly‐222 to Leu‐230) in the human thyrotropin receptor are involved in ligand binding. J. Biol. Chem. 266: 14926–14930, 1991.
 340. Nagayama, Y., H. L. Wadsworth, G. D. Chazenbal, D. Russo, P. Seto, and B. Rapoport. Thyrotropin‐luteinizing hormone/chorionic gonadotropin‐receptor extracellular domain chimeras as probes for thyrotropin receptor function. Proc. Natl. Acad. Sci. U.S.A. 88: 902–905, 1991.
 341. Nakanishi, S. Molecular diversity of glutamate receptors and implications for brain function. Science 258: 597–603, 1992.
 342. Namba T. Y. Sugimoto, M. Negishi, A. Irie, F. Ushikubi, A. Kakisuka, S. Ito, A. Ichikawa, and S. Narumiya. Splicing of C‐terminal tail of prostaglandin E receptor subtype EP3 determines G‐protein specificity. Nature 365: 155–170, 1993.
 343. Nathans, J. Determinants of visual pigment absorbance: identification of the retinylidene Schiff's base counterion in bovine rhodopsin. Biochemistry 29: 9746–9752, 1990.
 344. Nathans, J., and D. S. Hogness. Isolation and nucleotide sequence of the gene encoding human rhodopsin. Proc. Natl. Acad. Sci. U.S.A. 81: 4851–4855, 1984.
 345. Nathans, J., and D. S. Hogness. Isolation, sequence analysis, and intron‐exon arrangement of the gene encoding bovine rhodopsin. Cell 34: 807–814, 1983.
 346. Navon, S. E., and B. K.‐K. Fung. Characterization of transducin from bovine retinal rod outer segments. Mechanism and effects of cholera toxin–catalyzed ADP‐ribosylation. J. Biol. Chem. 259: 6686–6693, 1984.
 347. Neer, E. J. Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80: 249–257, 1995.
 348. Neer, E. J., C. J. Schmidt, R. Nambudripad, and T. F. Smith. The ancient regulatory‐protein family of WD‐repeat proteins. Nature 371: 297–300, 1994.
 349. Negishi, M., T. Namba, Y. Sugimoto, A. Irie, T. Katada, S. Narumiya, and A. Ichikawa. Opposite coupling of prostaglandin E receptor EP3C with Gs and G0. J. Biol. Chem. 268: 26067–26070, 1993.
 350. Negishi, M., Y. Sugimoto, A. Arie, S. Narumiya, and A. Ichikawa. Two isoforms of prostaglandin E receptor EP3 subtype. Different COOH‐terminal domains determine sensitivity to agonist‐induced desensitization. J. Biol. Chem. 268: 9517–9523, 1993.
 351. Neill, J. D., L. W. Duck, J. C. Sellers, L. C. Musgrove, A. Scheschonka, K. M. Druey, and J. H. Kherl. Potential role for a regulator of G protein signaling (RGS2) in gonadotropin releasing hormone (GnRH) stimulated desensitization. Endocrinology 138: 843–846, 1997.
 352. Neve, K. A., B. A. Cox, R. A. Henningsen, A. Spanoyannis, and R. L. Nerve. Pivotal role for aspartate‐80 in the regulation of dopamine D2 receptor affinity for drugs and inhibition of adenylyl cyclase. Mol. Pharmacol. 39: 733–739, 1991.
 353. Ng, G. Y., S. R. George, R. L. Zastawny, M. Caron, M. Bouvier, M. Dennis, and F. O. O'Dowd. Human serotonin 1B receptor expression in Sf9 cells: phosphorylation, palmitoylation, and adenylyl cyclase inhibition. Biochemistry 32: 11727–11733, 1993.
 354. Ng, G. Y., B. Mouillac, S. R. George, M. Caron, M. Dennis, M. Bouvier, and B. F. O'Dowd. Desensitization, phosphorylation and palmitoylation of the human dopamine D1 receptor. Eur. J. Pharmacol. 267: 7–19, 1994.
 355. Nishida, E., and Y. Gotoh. The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem. Sci. 18: 128–130, 1993.
 356. Nishizuka, Y. Studies and perspectives of protein kinase C. Science 233: 305–312, 1986.
 357. Noel, J. P., H. E. Hamm, and P. B. Sigler. The 2.2 Å crystal structure of transducin‐α complexed with GTPγs. Nature 366: 654–662, 1993.
 358. Nussenzveig, D. R., C. N. Thaw, and M. C. Gershengorn. Inhibition of inositol phosphate second messenger formation by intracellular loop one of a human calcitonin receptor. J. Biol. Chem. 269: 28123–28129, 1994.
 359. O'Dowd, B. F., M. Hnatowich, M. G. Caron, R. J. Lefkowitz, and M. Bouvier. Palmitoylation of the human β2‐adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J. Biol. Chem. 264: 7564–7569, 1989.
 360. O'Dowd, B. F., M. Hnatowich, J. W. Regan, W. M. Leader, M. G. Caron, and R. J. Lefkowitz. Site‐directed mutagenesis of the cytoplasmic domains of the human β2‐adrenergic receptor. J. Biol. Chem. 263: 15985–15992, 1988.
 361. Offermanns, S., and G. Schultz. What are the functions of the pertussis toxin‐insensitive G‐proteins G12, G13 and Gz. Mol. Cell. Endocrinol. 100: 71–74, 1994.
 362. Offermanns, S., and M. I. Simon. Gα15 and Gα16 couple to a wide variety of receptors to phospholipase C. J. Biol. Chem. 270: 15175–15180, 1995.
 363. Ohyama, K., Y. Yamano, S. Chaki, T. Kondo, and T. Inagami. Domains for G‐protein coupling in angiotensin II receptor type I: studies by site‐directed mutagenesis. Biochem. Biophys. Res. Commun. 189: 677–683, 1992.
 364. Okamoto, T., and I. Nishimoto. Detection of G protein‐activator regions in M4 subtype muscarinic cholinergic, and α2‐adrenergic receptors based upon characteristics in primary structure. J. Biol. Chem. 267: 8342–8346, 1992.
 365. Osawa, S., N. Dhanasekaran, C. W. Woon, and G. L. Johnson. Gαi‐Gαs chimeras define the function of α chain domains in control of G‐protein activation and βγ subunit complex interactions. Cell 63: 697–706, 1990.
 366. Ostrowski, J., M. A. Kjelsberg, M. G. Caron, and R. J. Lefkowitz. Mutagenesis of the β2‐adrenergic receptor: how structure elucidates function. Annu. Rev. Pharmacol. Toxicol. 32: 167–183, 1992.
 367. Ovchinnikov, Y. A., N. G. Abdulaev, and A. S. Bogachuk. Two adjacent cysteine residues in the C‐terminal cytoplasmic fragment of bovine rhodopsin are palmitoylated. FEBS Lett. 230: 1–5, 1988.
 368. Pace, U., E. Hanski, Y. Salomon, and D. Lancet. Odorant‐sensitive adenylate cyclase may mediate olfatory reception. Nature 316: 255–258, 1985.
 369. Pages F., P. Deterre, and C. Pfister. Enhanced GTPase activity of transducin when bound to cGMP phosphodiesterase in bovine retinal rods. J. Biol. Chem. 267: 22018–22021, 1992.
 370. Parenti, M., M. A. Vigano, C. M. H. Newman, G. Milligan, and A. I. Magee. A novel N‐terminal motif for palmitoylation of G‐protein α subunits. Biochem. J. 291: 349–353, 1993.
 371. Park, D., D.‐Y. Jhon, C.‐W. Lee, C.‐H. Lee, and S. G. Rhee. Activation of phospholipase C isoenzymes by G protein βγ subunits. J. Biol. Chem. 268: 4573–4577, 1993.
 372. Parker, E. M., K. Kameyama, T. Higashijima, and E. M. Ross. Reconstitutively active G protein–coupled receptors purified from baculovirus‐infected insect cells. J. Biol. Chem. 266: 519–527, 1991.
 373. Parma, J., L. Duprez, J. V. Sande, P. Cochaux, C. Gervy, J. Mokel, J. Dumont, and G. Vassart. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365: 649–651, 1993.
 374. Patel, D. R., Y. Kong, and S. P. Sreedharan. Molecular cloning and expression of a human secretin receptor. Mol. Pharmacol. 47: 467–473, 1995.
 375. Paulssen, E. J., R. H. Paulssen, K. M. Gautvik, and J. O. Gordeladze. “Cross‐talk” between phospholipase C and adenylyl cyclase involves regulation of G‐protein levels in GH3 rat pituitary cells. Cell. Signal. 4: 747–755, 1992.
 376. Paulssen, R. H., E. J. Paulssen, K. M. Gautvik, and J. O. Gordeladze. The thyroliberin receptor interacts directly with a stimulatory guanine‐nucleotide‐binding protein in the activation of adenylyl cyclase in GH3 rat pituitary tumour cells. Evidence obtained by the use of antisense RNA inhibition and immunoblocking of the stimulatory guanine‐nucleotide‐binding protein. Eur. J. Biochem. 204: 413–418, 1992.
 377. Pelech, S. L., and J. S. Sanghera. MAP kinases: charting the regulatory pathways. Science 257: 1355–1356, 1992.
 378. Perlman, J. H., L. Laakkonen, R. Osman, and M. C. Gershengorn. A model of the thyrotropin‐releasing hormone (TRH) receptor binding pocket. J. Biol. Chem. 269: 23383–23386, 1994.
 379. Peroutka, S. J. 5‐Hydroxytryptamine receptors. J. Neurochem. 60: 408–416, 1993.
 380. Phillips, W. J., and R. A. Cerione. Rhodopsin/transducin interactions. I. Characterization of the binding of the transducin‐βγ subunit complex to rhodopsin using fluorescence spectroscopy. J. Biol. Chem. 267: 17032–17039, 1992.
 381. Pin, J. P., and R. Duvoisin. The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34: 1–26, 1995.
 382. Pitcher, J. A., J. Inglese, J. B. Higgins, J. L. Arriza, P. J. Casey, C. Kim, J. L. Benovic, M. W. Kwatra, M. G. Caron, and R. J. Lefkowitz. Role of the βγ subunits of G‐proteins in targeting the β‐adrenergic receptor kinase to membrane‐bound receptors. Science 257: 1264–1267, 1992.
 383. Pitcher, J. A., E. S. Payne, C. Csortos, A. A. DePaoli‐Roach, and R. J. Lefkowitz. The G‐protein–coupled receptor phosphatase: a protein phosphatase type 2A with a distinct subcellular distribution and substrate specificity. Proc. Natl. Acad. Sci. U.S.A. 92: 8343–8347, 1995.
 384. Post, G. R., and J. H. Brown. G protein–coupled receptors and signaling pathways regulating growth responses. FASEB J. 10: 741–749, 1996.
 385. Premont, R. T., J. Inglese, and R. L. Lefkowitz. Protein kinases that phosphorylate activated G protein–coupled receptors. FASEB J. 9: 175–182, 1995.
 386. Probst, W. C., L. A. Snyder, D. I., Schuster, J. Brosius, and S. C. Seaflon. Sequence alignment of the G‐protein coupled receptor superfamily. DNA Cell Biol. 11: 1–11, 1992.
 387. Pronin, A. N., and N. Gautman. Interaction between G‐protein β and γ subunit types is selective. Proc. Natl. Acad. Sci. U.S.A. 89: 6220–6224, 1992.
 388. Pumiglia, K. M., H. LeVine, T. Haske, T. Habib, R. Jove, and S. J. Decker. A direct interaction between G‐protein βγ subunits and the Raf‐1 protein kinase. J. Biol. Chem. 270: 14251–14254, 1995.
 389. Quintana, J., R. W. Hipkin, J. Sanchez‐Yague, and M. Ascoli. Follitropin (FSH) and phorbol ester stimulate the phosphorylation of the FSH receptor in intact cells. J. Biol. Chem. 269: 8722–8779, 1994.
 390. Rahmatullah, M., and J. D. Robishaw. Direct interaction of the α and subunits of the G‐proteins. J. Biol. Chem. 269: 3574–3580, 1994.
 391. Ramdas, L., R. M. Disher, and T. G. Wensel. Nucleotide exchange and cGMP phosphodiesterase activation by pertussis toxin inactivated transducin. Biochemistry 30: 11637–11645, 1991.
 392. Rands, R., M. R. Candelore, A. H. Cheung, W. S. Hill, D. C. Strader, and R. A. F. Dixon. Mutational analysis of β‐adrenergic receptor glycosylation. J. Biol. Chem. 265: 10759–10764, 1990.
 393. Rao, V. R., G. B. Cohen, and D. D. Oprian. Rhodopsin mutation G90D and a molecular mechanism for congenital blindness. Nature 367: 639–642, 1994.
 394. Rarick, H. M., N. O. Artemyev, and H. E. Hamm. A site on rod G protein α subunit that mediates effector activation. Science 256: 1031–1033, 1992.
 395. Rawlings, S. R. PACAP, PACAP receptors, and intracellular signaling. Mol. Cell. Endocrinol. 101: C5–C9, 1994.
 396. Ray, K., C. Kunsch, L. M. Bonner, and J. D. Robishaw. Isolation of cDNA clones enconding eight different human G protein γ subunits, including three novel forms designated the γ4, γ10 and γ11 subunits. J. Biol. Chem. 270: 21765–21771, 1995.
 397. Raymond, J. R. Multiple mechanisms of receptor‐G protein signaling specificity. Am. J. Physiol. 269 (Renal Fluid Electrolyte Physiol. 40): F141–F158, 1995.
 398. Raymond, J. R., C. L. Olsen, and T. W. Gettys. Cell‐specific physical and functional coupling of human 5‐HT1A receptors to inhibitory G protein α subunits and lack of coupling to Gsα. Biochemistry 32: 11064–11073, 1993.
 399. Reed, R. R. How does the nose know? Cell 60: 1–2, 1990.
 400. Reinhart, J., L. M. Mertz, and K. J. Catt. Molecular cloning and expression of cDNA encoding the murine gonadotropin‐releasing hormone receptor. J. Biol. Chem. 267: 21281–21284, 1992.
 401. Ren, Q., H. Kurose, R. J. Lefkowitz, and S. Cotecchia. Constitutively active mutants of the α2‐adrenergic receptor. J. Biol. Chem. 268: 16483–16487, 1993.
 402. Rens‐Domiano, S., and H. E. Hamm. Structural and functional relationships of heterotrimeric G‐proteins. FASEB J. 9: 1059–1066, 1995.
 403. Richardson, R. M., and M. M. Hosey. Agonist‐induced phosphorylation and desensitization of human m2 cholinergic receptors in Sf9 insect cells. J. Biol. Chem. 267: 22249–22255, 1992.
 404. Robbins, L. S., J. H. Nadeau, K. R. Johnson, M. A. Kelly, L. Roselli‐Rehfuss, E. Baack, K. G. Mountjoy, and R. D. Cone. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72: 827–834, 1993.
 405. Rodbell, M. Signal transduction: evolution of an idea. Environ. Health Perspect. 103: 338–345, 1995.
 406. Ross, E. M. G protein GTPase‐activating proteins: regulation of speed, amplitude, and signaling selectivity. Recent Prog. Horm. Res. 50: 207–221, 1995.
 407. Roth, N. S., P. T. Campbell, M. G. Caron, R. J. Lefkowitz, and M. J. Lohse. Comparative rates of desensitization of β‐adrenergic receptors by the β‐adrenergic receptor kinase and the cyclic AMP‐dependent protein kinase. Proc. Natl. Acad. Sci. U.S.A. 88: 6201–6204, 1991.
 408. Ryu, K.‐S., R. L. Gilchrist, I. Ji, S.‐J. Kim, and T. H. Ji. Exoloop 3 of the luteinizing hormone/choriogonadotropin receptor. Lys583 is essential and irreplaceable for human choriogonadotropin (hCG)–dependent receptor activation but not for high affinity hCGbinding. J. Biol. Chem. 271: 7301–7304, 1996.
 409. Sadoshima, J., and S. Izumo. The heterotrimeric Gq protein–coupled angiotensin II receptor activates p21ras via the tyrosine kinase Shc‐Grb‐Sos pathway in cardiac myocytes. EMBO J. 15: 775–787, 1996.
 410. Sakmar, T. P., R. R. Franke, and H. G. Khorana. Glutamic acid‐113 serves as the retinylidene Schiff base counterion in bovine rhodopsin. Proc. Natl. Acad. Sci. U.S.A. 86: 8309–8313, 1989.
 411. Sakmar, T. P., R. R. Franke, and H. G. Khorana. The role of the retinylidene Schiff base counterion in rhodopsin in determining wavelength absorbance and Schiff base pKa. Proc. Natl. Acad. Sci. U.S.A. 88: 3079–3083, 1991.
 412. Samama, P., S. Cotecchia, T. Costa, and R. J. Lefkowitz. A mutation‐induced activated state of the β2‐adrenergic receptor. Extending the ternary complex model. J. Biol. Chem. 268: 4625–4636, 1993.
 413. Sanford, J., J. Codina, and L. Birnbaumer. γ‐Subunits of G proteins, but not their α‐ or β‐subunits, are polyisoprenylated. Studies on post‐translational modifications using in vitro translation with rabbit reticulocyte lysates. J. Biol. Chem. 266: 9570–9579, 1991.
 414. Schafer, W. R., and J. Rine. Protein prenylation: genes, enzymes, targets and functions. Annu. Rev. Genet. 25: 209–238, 1992.
 415. Schelling, J. R., A. S. Hanson, R. Marzen, and S. L. Linas. Cytoskeleton‐dependent endocytosis is required for apical‐type angiotensin II receptor‐mediated phospholipase C activation in cultured rat proximal tubule cells. J. Clin. Invest. 90: 2472–2480, 1992.
 416. Schertler, G.F.X., C. Villa, and R. Henderson. Projection structure of rhodopsin. Nature 362: 770–772, 1993.
 417. Schipani, E., H. Karga, A. C. Karaplis, J. T. Potts, Jr., H. M. Kronenberg, G. V. Segre, A. B. Abou‐Samra, and H. Jüppner. Identical complementary deoxyribonucleic acids encode a human renal and bone parathyroid hormone (PTH)/PTH‐related peptide receptor. Endocrinology 132: 2157–2165, 1993.
 418. Schleicher, S., I. Boekhoff, J. Arriza, R. J. Lefkowitz, and H. Breer. A β‐adrenergic receptor kinase‐like enzyme is involved in olfatory signal termination. Proc. Natl. Acad. Sci. U.S.A. 90: 1420–1424, 1993.
 419. Schmidt, C. J., T. C. Thomas, M. A. Levine, and E. J. Neer. Specificity of G‐protein β and γ subunit interaction. J. Biol. Chem. 267: 13807–13810, 1992.
 420. Schramm, M., and Z. Selinger. Message transmission: receptor controlled adenylate cyclase system. Science 225: 1350–1356, 1984.
 421. Schvarts, I., and E. Hazum. Tunicamycin and neuraminidase effects of luteinizing hormone (LH)‐releasing hormone binding and LH release from rat pituitary cels in culture. Endocrinology 116: 2341–2346, 1985.
 422. Scott, R. H., and A. C. Dolphin. Activation of a G‐protein promotes agonist responses to calcium channel ligands. Nature 330: 760–762, 1987.
 423. Seaflon, S. C., and R. P. Millar. The gonadotrophin‐releasing hormone receptor: structural determinants and regulatory control. Hum. Reprod. Update 1: 216–230, 1995.
 424. Segaloff, D. L., and M. Ascoli. The lutropin/choriogonadotropin receptor … 4 years later. Endocr. Rev. 14: 324–347, 1993.
 425. Segaloff, D. L., R. Sprengel, K. Nikolics, and M. Ascoli. The structure of the lutropin/choriogonadotropin receptor. Recent Prog. Horm. Res. 46: 261–303, 1990.
 426. Sevetson, B. R., X. Kong, and J. C. Lawrence, Jr. Increasing cAMP attenuates activation of mitogen‐activated protein kinase. Proc. Natl. Acad. Sci. U.S.A. 90: 10305–10309, 1993.
 427. Shah, B. H., D. J. MacEwan, and G. Milligan. Gonadotrophin‐releasing hormone receptor agonist‐mediated down‐regulation of Gqα/G11α (pertusis toxin‐insensitive) G proteins in αT3–1 gonadotroph cells reflects increased G protein turnover but not alterations in mRNA levels. Proc. Natl. Acad. Sci. U.S.A. 92: 1886–1890, 1995.
 428. Shapiro, R. A., and N. M. Nathanson. Deletion analysis of the mouse m1 muscarinic acetylcholine receptor: effects on phosphoinositide metabolism and down‐regulation. Biochemistry 28: 8946–8950, 1989.
 429. Shear, M., P. A. Insel, K. L. Melmon, and P. Coffino. Agonist‐specific refractoriness induced by isoproterenol: studies with mutant cells. J. Biol. Chem. 251: 7572–7576, 1976.
 430. Shenker, A., L. Laue, S. Kosugl, J. Merendino, Jr., T. Minegishi, and G. B. Cutler. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365: 652–654, 1993.
 431. Shinozawa, T., S. Uchida, E. Martin, D. Cafiso, W. Hubbell, and M. Bitensky. Additional component required for activity and reconstitution of light activated vertebrate photoreceptor GTPase. Proc. Natl. Acad. Sci. U.S.A. 77: 1408–1411, 1980.
 432. Simon, M. A., G. S. Dodson, and G. M. Rubin. An SH3‐SH2‐SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro. Cell 73: 169–177, 1993.
 433. Simon, M. I., P. Strathmann, and N. Gautam. Diversity of G proteins in signal transduction. Science 252: 802–808, 1991.
 434. Simonds, W. F., J. E. Butrynski, N. Gautam, C. G. Unsion, and A.M. Spiegel. G‐protein βγ dimers. Membrane targeting requires subunit co‐expression and intact γ CAAX domain. J. Biol. Chem. 266: 5363–5366, 1991.
 435. Simonds, W. F., P. K. Goldsmith, J. Codina, C. G. Unson, and A. M. Spiegel. Gi2 mediates α2‐adrenergic inhibition of adenylyl cyclase in platelet membranes: in situ identification with Gα C‐terminal antibodies. Proc. Natl. Acad. Sci. U.S.A. 86: 7809–7813, 1989.
 436. Smrcka, A. V., J. R. Helper, K. O. Brown, and P. C. Sternweiss. Regulation of polyphosphoinositide‐specific phospholipase C activity by purifed Gq. Science 251: 804–807, 1991.
 437. Smrcka, A. V., and P. C. Sternweis. Regulation of purified subtypes of phosphatidylinositol‐specific phospholipase Cβ by G protein α and βγ subunits. J. Biol. Chem. 268: 9667–9674, 1993.
 438. Sondek, J., A. Bohm, D. G. Lambright, H. E. Hamm, and P. B. Sigler. Crystal structure of a GA protein βγ dimer at 2.1 Å resolution. Nature 379: 369–374, 1996.
 439. Sondek, J., D. G. Lambright, J. P. Noel, H. E. Hamm, and P. B. Sigler. GTPase mechanism of G proteins from the 1.7‐Å crystal structure of transducin α−GDP−AlF−4. Nature 372: 276–279, 1994.
 440. Spalding, T., N. Birdsall, C. Curtis, and E. Hulme. Acetylcholine mustard labels the binding site aspartate in muscarinic acetylcholine receptors. J. Biol. Chem. 269: 4092–4097, 1994.
 441. Spengler, D., C. Waeber, C. Pantaloni, F. Holsboer, J. Bockaert, P. H. Seburg, and L. Journot. Differential signal transduction by five splice variants of the PACAP receptor. Nature 365: 170–175, 1993.
 442. Spiegel, A. M. Defects in G protein–coupled signal transduction in human disease. Annu. Rev. Physiol. 58: 143–170, 1995.
 443. Spiegel, A. M., P. S. Backlund, J. E. Butyrinski, T. L. Z. Jones, and W. F. Simonds. The G protein connection: molecular basis of membrane association. Trends Biochem. Sci. 16: 338–341, 1991.
 444. Spiegel, A. M., A. Shenker, and L. S. Weinstein. Receptor‐effector coupling by G proteins: implications for normal and abnormal signal transduction. Endocr. Rev. 13: 536–565, 1992.
 445. Spring, D. J., and E. J. Neer. A 14 amino acid region of the G protein γ subunit is sufficient to confer the selectivity of α binding to the β subunit. J. Biol. Chem. 269: 22882–22886, 1994.
 446. Stanislaus, D., J. A. Janovick, S. Brothers, and P. M. Conn. Regulation of Gq/11α by the gonadotropin‐releasing hormone receptor. Mol. Endocrinol. 11: 738–746, 1997.
 447. Sterne‐Marr, R., and J. L. Benovic. Regulation of G protein–coupled receptors by receptor kinases and arrestins. Vitam. Horm. 51: 193–234, 1995.
 448. Stiles, G. L., J. L. Benovic, M. G. Caron, and R. J. Lefkowitz. Mammalian beta‐adrenergic receptors, distinct glycoprotein populations containing high mannose or complex type carbohydrate chains. J. Biol. Chem. 259: 8655–8663, 1984.
 449. Stoffel, R. H., R. R. Randall, R. T. Premont, R. J. Lefkowitz, and J. Inglese. Palmitoylation of G protein–coupled receptor kinase, GRK6: lipid modification diversity in the GRK family. J. Biol. Chem. 269: 27791–27794, 1994.
 450. Stone, D. E., G. M. Cole, M. De Barros Lopez, M. Goebl, and S. I. Reed. N‐Myristoylation is required for function of the pheromone‐responsive Gα protein of yeast: conditional activation of the pheromone response by a temperature‐sensitive N‐myristoyl transferase. Genes Dev. 5: 1969–1981, 1991.
 451. Strader, C. D., M. R. Candelore, W. S. Hill, I. S. Sigal, and R. A. Dixon. Identification of two serine residues involved in agonist activation of the β‐adrenergic receptor. J. Biol. Chem. 264: 13572–13578, 1989.
 452. Strader, C. D., R. A. Dixon, A. H. Cheung, M. R. Candelore, A. D. Blake, and I. S. Sigal. Mutations that uncouple the β‐adrenergic receptor from Gs and increase agonist affinity. J. Biol. Chem. 262: 16439–16443, 1987.
 453. Strader, C. D., T. M. Fong, M. P. Graziano, and M. R. Tota. The family of G‐protein–coupled receptors. FASEB J. 9: 745–754, 1995.
 454. Strader, C. D., T. M. Fong, M. R. Tota, and D. Underwood. Structure and function of G protein–coupled receptors. Annu. Rev. Biochem. 63: 101–132, 1994.
 455. Strader, C. D., T. Gaffney, E. E. Sugg, M. R. Candelore, R. Keys, A. A. Patchett, and R.A.F. Dixon. Allele‐specific activation of genetically engineered receptors. J. Biol. Chem. 266: 5–8, 1991.
 456. Strader, C. D., I. S. Sigal, M. R. Candelore, E. Rands, W. S. Hill, and R.A.F. Dixon. Conserved aspartate residues 79 and 113 of the β‐adrenergic receptor have different roles in receptor function. J. Biol. Chem. 263: 10267–10271, 1988.
 457. Strader, C. D., I. S. Sigal, and R.A.F. Dixon. Genetic approaches to the determination of structure‐function relationships of G protein–coupled receptors. Trends Pharmacol. Sci. (): 26–30, 1989.
 458. Strader, S. D., I. S. Sigal, and R. A. Dixon. Mapping the functional domains of the β‐adrenergic receptor. Am. J. Resp. Cell Mol. Biol. 1: 81–86, 1989.
 459. Strader, C. D., I. S. Sigal, R. B. Register, M. R. Candelore, E. Rands, and R. A. Dixon. Identification of residues required for ligand binding to the β‐adrenergic receptor. Proc. Natl. Acad. Sci. U.S.A. 84: 4384–4388, 1987.
 460. Strathmann, M., and M. I. Simon. G protein diversity: a distinct class of α subunits is present in vertebrates and invertebrates. Proc. Natl. Acad. Sci. U.S.A. 87: 9113–9117, 1990.
 461. Stryer, L. Visual excitation and recovery. J. Biol. Chem. 266: 10711–10714, 1991.
 462. Stryer, L., J. B. Hurley, and B. K. Fung. Transducin and the cyclic GMP phosphodiesterase of retinal rod outer segments. Methods Enzymol. 96: 617–627, 1983.
 463. Su, Y.‐F., T. K. Harden, and J. P. Perkins. Catecholamine‐specific desensitization of adenylate cyclase: evidence for a multistep process. J. Biol. Chem. 255: 7410–7419, 1980.
 464. Sullivan, K. A., R. T. Miller, S. B. Masters, B. Beiderman, W. Heideman, and H. R. Bourne. Identification of receptor contact site involved in receptor‐G protein coupling. Nature 330: 758–760, 1987.
 465. Sunahara, R. K., C. W. Dessauer, and A. G. Gilman. Complexity and diversity of mammalian adenylyl cyclases. Annu. Rev. Pharmacol. Toxicol. 36: 461–480, 1996.
 466. Suprenant, A., D. A. Horstman, H. Akbarali, and L. E. Limbird. A point mutation of the α2‐adrenoceptor that blocks coupling to potassium but not calcium currents. Science 257: 977–980, 1992.
 467. Suzuki, H., G. N. Prado, N. Wilkinson, and J. Navarro. The N‐terminus of interleukin‐8 (IL‐8) receptor confers high affinity binding to human IL‐8. J. Biol. Chem. 269: 18263–18266, 1994.
 468. Takeuchi, K., N. Takahashi, T. Abe, and K. Abe. Two isoforms of the rat kidney EP3 receptor derived by alternative RNA splicing: intrarenal expression co‐localization. Biochem. Biophys. Res. Commun. 199: 834–840, 1994.
 469. Tanabe, Y., M. Masu, T. Ishii, R. Shigemoto, and S. Nakanishi. A family of metabotropic glutamate receptors. Neuron 8: 169–179, 1992.
 470. Tang, W.‐J., and A. G. Gilman. Type‐specific regulation of adenylyl cyclase by G protein βγ subunits. Science 254: 1500–1504, 1991.
 471. Tang, W.‐J., and A. G. Gilman. Adenylyl cyclases. Cell 70: 869–872, 1992.
 472. Tapanainen, J. S., M. Bo, L. Dunkel, H. Billig, E. A. Perlas, I. Boime, and A.J.W. Hsueh. Deglycosylation of the human luteinizing hormone receptor does not affect ligand binding and signal transduction. Endocr. J. 1: 219–225, 1993.
 473. Taussig, R., J. A. Iñiguez‐Lluhi, and A. G. Gilman. Inhibition of adenylyl cyclase by Gαi. Science 261: 218–221, 1993.
 474. Taussig, R., L. M. Quarmby, and A. G. Gilman. Regulation of purified type‐I and type‐II adenylyl cyclases by G protein βγ subunits. J. Biol. Chem. 268: 9–12, 1993.
 475. Taussig, R., W.‐J. Tang, J. R. Hepler, and A. G. Gilman. Distinct patterns of bidirectional regulation of mammalian adenylyl cyclases. J. Biol. Chem. 269: 6093–6100, 1994.
 476. Thomas, D., T. G. Rozell, X. Liu, and D. L. Segaloff. Mutational analyses of the extracellular domain of the full‐length lutropin/choriogonadotropin receptor suggest leucine‐rich repeats 1–6 are involved in hormone binding. Mol. Endocrinol. 10: 760–768, 1996.
 477. Thomas, D. D., and L. Stryer. Transverse location of the retinal chromophore of rhodopsin in rod outer segment disc membranes. J. Mol. Biol. 154: 145–157, 1982.
 478. Thomas, T. C., C. J. Schmidt, and E. J. Neer. G protein α0 subunit: mutation of conserved cysteines identifies a subunit contact surface and alters GDP affinity. Proc. Natl. Acad. Sci. U.S.A. 90: 10295–10299, 1993.
 479. Thompson, P., and J.B.C. Findlay. Phosphorylation of ovine rhodopsin. Biochem J. 220: 773–780, 1984.
 480. Thorens, B. Expression cloning of the pancreatin β cell receptor for the gluco‐incretin hormone glucagon‐like peptide. Proc. Natl. Acad. Sci. U.S.A. 89: 8641–8645, 1992.
 481. Tota, M. R., and C. D. Strader. Characterization of the binding domain of the β‐adrenergic receptor with the fluorescent antagonist carazolol. Evidence for a buried ligand binding site. J. Biol. Chem. 265: 16891–16897, 1990.
 482. Touhara, K., B. E. Hawes, T. Van Biesen, and R. J. Lefkowitz. G protein βγ subunits stimulate phosphorylation of Shc adapter protein. Proc. Natl. Acad. Sci. U.S.A. 92: 9284–9287, 1995.
 483. Trumpp‐Kallmeyer, S., B. Chini, B. Mouillac, C. Barberis, J. Hoflack, and M. Hibert. Towards understanding the role of the first extracellular loop for the binding of peptide hormones to G‐protein coupled receptors. Pharm. Acta Helv. 70: 255–262, 1995.
 484. Tsai‐Morris, C. H., E. Buczko, W. Wang, and M. L. Dufau. Intronic nature of the rat luteinizing hormone receptor gene defines a soluble receptor subspecies with hormone binding activity. J. Biol. Chem. 265: 19385–19388, 1990.
 485. Tsai‐Morris, C. H., E. Buczko, W. Wang, X. Z. Xie, and M. L. Dufau. Structural organization of the rat luteinizing hormone (LH) receptor gene. J. Biol. Chem. 266: 11355–11359, 1991.
 486. Ullrich, A., and J. Schlessinger. Signal transduction by receptor with tyrosine kinase activity. Cell 61: 203–212, 1990.
 487. Vaillancourt, R. R., A. M. Gardner, and G. L. Johnson. B‐Rafdependent regulation of the MEK‐1/mitogen‐activated protein kinase pathway in PC12 cells and regulation by cyclic AMP. Mol. Cell. Biol. 14: 6522–6530, 1994.
 488. Van Biesen, T., B. E. Hawes, D. K. Luttrell, K. M. Krueger, K. Touhara, E. Porfiri, M. Sakaue, L. M. Luttrell, and R. J. Lefkowitz. Receptor‐tyrosine‐kinase‐ and Gβγ‐mediated MAP kinase activation by a common signalling pathway. Nature 376: 781–784, 1995.
 489. Van Biesen, T. M., L. M. Luttrell, B. E. Hawes, and R. J. Lefkowitz. Mitogenic signaling via G protein–coupled receptors. Endocr. Rev. 17: 698–714, 1996.
 490. Van Corven, E. J., P. L. Hordijk, R. H. Medema, J. L. Bos, and W. H. Moolenaar. Pertussis toxin–sensitive activation of p21ras by G protein–coupled receptor agonist in fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 90: 1257–1261, 1993.
 491. Van Dop, C., M. Tsubokawa, H. R. Bourne, and J. Ramachandran. Amino acid sequence of retinal transducin at the site ADP‐ribosylated by cholera toxin. J. Biol. Chem. 259: 696–699, 1984.
 492. Van Koppen, C. J., and N. M. Nathanson. The cysteine residue in the carboxy‐terminal domain of the m2 muscarinic acetylcholine receptor is not required for receptor‐mediated inhibition of adenylate cyclase. J. Neurochem. 57: 1873–1877, 1991.
 493. Van Sande, J., E. Raspe, J. Perret, C. Lejeune, C. Maenhaut, G. Vassar, and J. E. Dumont. Thyrotropin activates both the cAMP and the PIP2 cascades in CHO cells expressing the human cDNA of the TSH receptor. Mol. Cell. Endocrinol. 74: R1–R6, 1990.
 494. Vara Prasad, M.V.V.S., J. M. Dermott, L. E. Heasley, G. L. Johnson, and N. Dhanasekaran. Activation of Jun kinase/stress‐activated protein kinase by GTPase‐deficient mutants of Gα12 and Gα13. J. Biol. Chem. 270: 18655–18659, 1995.
 495. Vassart, G., L. Desarnaud, L. Duprez, D. Eggerickx, O. Labbé, F. Libert, C. Mollerau, J. Parma, R. Paschke, M. Tonacchera, P. Vanderhaeghen, J. Van Sande, J. Dumont, and M. Parmentier. The G protein–coupled receptor family and one of its members, the TSH receptor. Ann. N.Y. Acad. Sci. 766: 23–30, 1995.
 496. Von Weizsαcker, E., M. P. Strathmann, and M. I. Simon. Diversity among the β subunits of heterotrimeric GTP‐binding proteins: characterization of a novel β‐subunit. Biochem. Biophys. Res. Commun. 183: 350–356, 1992.
 497. von Zastrow, M., and B. K. Kobilka. Ligand‐regulated internalization and recycling of human β2‐adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors. J. Biol. Chem. 267: 3530–3538, 1992.
 498. von Zastrow, M., R. Link, D. Daunt, G. Barsh, and B. K. Kobilka. Subtype specific differences in the intracellular sorting of G protein–coupled receptors. J. Biol. Chem. 268: 763–766, 1993.
 499. Voyno‐Yasenetskaya, T., B. R. Conklin, R. L. Gilbert, R. Hooley, H. R. Bourne, and D. L. Barber. Gα13 stimulates NaH exchange. J. Biol. Chem. 269: 4721–4724, 1994.
 500. Vuong, T. M., and M. Chabre. Deactivation kinetics of the transduction cascade of vision. Proc. Natl. Acad. Sci. U.S.A. 88: 9813–9817, 1991.
 501. Wadsworth, H. L., G. D. Chazenbalk, Y. Nagayama, D. Russo, and B. Rapoport. An insertion in the human thyrotropin receptor critical for high affinity hormone binding. Science 249: 1423–1425, 1990.
 502. Wall, M. A., D. E. Coleman, E. Lee, J. A. Iñiguez‐Lluhi, B. A. Posner, A. G. Gilman, and S. R. Sprang. The structure of the G protein heterotrimer Giα1β1γ2. Cell 83: 1047–1068, 1995.
 503. Wang, C. D., M. A. Buck, and C. M. Fraser. Site‐directed mutagenesis of α2A‐adrenergic receptors: identification of amino acids involved in ligand binding and receptor activation by agonists. Mol. Pharmacol. 40: 168–179, 1991.
 504. Wang, D. S., R. Shaw, J. C. Winkelmann, and G. Shaw. Binding of PH domains of β‐adrenergic receptor kinase and β‐spectrin to WD40/β‐transducin repeat containing regions of the β‐subunit of trimeric G‐proteins. Biochem. Biophys. Res. Commun. 203: 29–35, 1994.
 505. Wang, Z., R. W. Hipkin, and M. Ascoli. Progressive cytoplasmic tail truncations of the lutropin‐choriogonadotropin receptor prevent agonist‐ or phorbol ester‐induced phosphorylation, impair agonist‐ or phorbol ester‐induced desensitization, and enhance agonist‐induced receptor down‐regulation. Mol. Endocrinol. 10: 748–759, 1996.
 506. Wang, Z., X. Liu, and M. Ascoli. Phosphorylation of the lutropin/choriogonadotropin receptor facilitates uncoupling of the receptor from adenylyl cyclase and endocytosis of the bound hormone. Mol. Endocrinol. 11: 183–192, 1997.
 507. Watson, A. J., A. Katz, and M. I. Simon. A fifth member of the mammalian G‐protein β‐subunit family. J. Biol. Chem. 269: 22150–22156, 1994.
 508. Watson, N., M. E. Liknder, K. M. Druey, J. H. Kehrl, and K. J. Blumer. RGS family members: GTPase‐activating proteins for heterotrimeric G‐protein α‐subunits. Nature 383: 172–177, 1996.
 509. Wedegaertner, P. B., and H. R. Bourne. Activation and depalmitoylation of Gsα. Cell 77: 1063–1070, 1994.
 510. Wedegaertner, P. B., H. R. Bourne, and M. von Zastrow. Activation‐induced subcellular redistribution of Gsα. Mol. Biol. Cell 7: 1225–1233, 1996.
 511. Wedegaertner, P. B., D. H. Chu, P. T. Wilson, M. J. Levis, and H. R. Bourne. Palmitoylation is required for signaling functions and membrane attachment of Gqα and Gsα. J. Biol. Chem. 268: 25001–25008, 1993.
 512. Wess, J. Molecular basis of muscarinic acetylcholine receptor function. Trends Pharmacol. Sci. 14: 308–313, 1993.
 513. Wess, J., T. I. Bonner, F. Dörje, and M. R. Brann. Delineation of muscarinic receptor domains conferring selectivity of coupling to guanine nucleotide–binding proteins and second messengers. Mol. Pharmacol. 38: 517–523, 1990.
 514. Wess, J., M. R. Brann, and T. I. Bonner. Delineation of muscarinic receptor domains conferring selectivity of coupling to guanine nucleotide–binding proteins and second messengers. FEBS Lett. 358: 133–136, 1989.
 515. Wess, J., D. Gdula, and M. R. Brand. Site‐directed mutagenesis of the m3 muscarinic receptor: identification of a series of threonine and tyrosine residues involved in agonist but not antagonist binding. EMBO J. 10: 3729–3734, 1991.
 516. West, R. E., J. Moss, M. Vaughan, T. Lui, and T. Y. Lin. Pertussis toxin‐catalyzed ADP‐ribosylation of transducin. Cysteine‐347 is the ADP ribose acceptor site. J. Biol. Chem. 260: 14428–14430, 1985.
 517. Wheeler, G. L., and M. W. Bitensky. A light‐activated GTPase in vertebrate photoreceptors: regulation of light‐activated cyclic GMP phosphodiesterase. Proc. Natl. Acad. Sci. U.S.A. 74: 4238–4242, 1977.
 518. Wheeler, M. B., M. Lu, J. S. Dillon, X.‐H. Leng, C. Cheng, and A. E. Boyd III. Functional expression of the rat glucagon‐like peptide‐I receptor: evidence for coupling to both adenylyl cyclase and phospholipase C. Endocrinology 133: 57–62, 1993.
 519. Wickman, K., and D. E. Clapham. Ion channel regulation by G proteins. Physiol. Rev. 75: 865–885, 1995.
 520. Wickman, K. D., J. Iñiguez‐Lluhi, P. Davenport, R. A. Taussig, G. B. Krapivinsky, M. E. Linder, A. Gilman, and D. E. Clapham. Recombinant Gβγ activates the muscarinic‐gated atrial potassium channel IKACh. Nature 368: 255–257, 1994.
 521. Wieland, T., B. Nurnberg, I. Ulibarri, S. Kaldenberg‐Stasch, G. Schultz, and K. H. Jakobs. Guanine nucleotide–specific phosphate transfer by guanine nucleotide–binding regulatory protein β‐subunits: characterization of the phosphorylated amino acid. J. Biol. Chem. 268: 18111–18118, 1993.
 522. Wilcox, C., J.‐S. Hu, and E. N. Olson. Acylation of proteins with myristic acid occurs cotranslationally. Science 238: 1275–1278, 1987.
 523. Wilden, U., S. W. Hall, and H. Kuhn. Phosphodiesterase activation by photoexcited rhodopsin is quenched when rhodopsin is phosphorylated and binds the intrinsic 48‐kDA protein of rod outer segments. Proc. Natl. Acad. Sci. U.S.A. 83: 1174–1178, 1986.
 524. Wilden, U., and H. Kuhn. Light‐dependent phosphorylation of rhodopsin: number of phosphorylation sites. Biochemistry 21: 3014–3022, 1982.
 525. Wilkie, T. M., P. A. Scherle, M. P. Strathmann, V. Z. Slepak, and M. I. Simon. Characterization of G‐protein α subunits in the Gq class: expression in murine tissues and in stromal and hematopoietic cell lines. Proc. Natl. Acad. Sci. U.S.A. 88: 10049–10053, 1991.
 526. Winitz, S., M. Russell, N, Qian, A. Gardner, L. Dwyer, and G. L. Johnson. Involvement of Ras and Raf in the Gi‐coupled acetylcholine muscarinic m2 receptor activation of mitogen‐activated protein (MAP) kinase kinase and MAP kinase. J. Biol. Chem. 268: 19196–19199, 1993.
 527. Wise, A., M.‐A. Watson‐Koken, S. Rees, M. Lee, and G. Milligan. Interactions of the α2A‐adrenoceptor with multiple Gi‐family G‐proteins: studies with pertussis toxin‐resistant G‐protein mutants. Biochem. J. 321: 721–728, 1997.
 528. Wong, S. K.‐F., E. M. Parker, and E. M. Ross. Chimeric muscarinic cholinergic: β‐adrenergic receptors that activate Gs in response to muscarinic agonist. J. Biol. Chem. 265: 6219–6224, 1990.
 529. Wong, S. K.‐F., C. Slaughter, A. E. Ruoho, and E. M. Ross. The catecholamine binding site of the β‐adrenergic receptor is formed by juxtaposed membrane‐spanning domains. J. Biol. Chem. 263: 7925–7928, 1988.
 530. Wong, Y. H., B. R. Conklin, and H. R. Bourne. Gz‐mediated hormonal inhibition of cyclic AMP accumulation. Science 255: 339–341, 1992.
 531. Wong, Y. H., A. Federman, A. M. Pace, I. Zachary, T. Evans, J. Pouyssegur, and H. R. Bourne. Mutant α subunits of Gi2 inhibit cyclic AMP accumulation. Nature 351: 63–65, 1991.
 532. Wu, D., C. H. Lee, S. G. Ree, and M. I. Simon. Activation of phospholipase C by the α subunits of Gq and G11 proteins in transfected Cos‐7 cells. J. Biol. Chem. 267: 1811–1817, 1992.
 533. Yang, K., and N. Gautman. Structural determinants for interaction with three different effectors on the G protein β subunit. J. Biol. Chem. 272: 2056–2059, 1997.
 534. Yatani, A., J. Codina, Y. Imoto, J. P. Reeves, L. Birnbaumer, and A. M. Brown. A G‐protein directly regulates mammalian cardiac calcium channels. Science 238: 1288–1292, 1987.
 535. Yatani, A., R. Mattera, J. Codina, R. Graf, K. Okabe, E. Padrell, R. Iyenegar, A. M. Brown, and L. Birnbaumer. The G protein–gated atrial K+ channel is stimulated by three distinct Giα subunits. Nature 336: 680–682, 1988.
 536. Yi, F., B. M. Denker, and E. J. Neer. Structural and functional studies of cross‐linked G0 protein subunits. J. Biol. Chem. 266: 2900–3906, 1991.
 537. Ykota, Y., C. Akazawa, H. Ohkubo, and S. Nakanishi. Delineation of structural domains involved in the subtype specificity of the tachykinin receptors through chimeric formation of substance P/substance K receptors. EMBO J. 11: 3585–3591, 1992.
 538. Yuzaki, M., and K. Mikoshiba. Pharmacological and immunocytochemical characterization of metabotropic glutamate receptors in cultured Purkinje cells. J. Neurosci. 12: 4253–4263, 1992.
 539. Zhang, R., C. H. Tsai‐Morris, M. Kitamura, E. Buczko, and M. L. Dufau. Changes in binding activity of luteinizing hormone receptors by site directed mutagenesis of potential glycosylation sites. Biochem. Biophys. Res. Commun. 181: 804–808, 1991.
 540. Zhang, S., O. A. Coso, C. Lee, J. S. Gutkind, and W. F. Simonds. Selective activation of effector pathways by brain‐specific G protein β5. J. Biol. Chem. 271: 33575–33579, 1996.
 541. Zheng, F., and J. P. Gallagher. (1S,3R)‐1‐Aminocyclopentane‐1,3‐dicarboxylic acid‐induced burst firing is mediated by native pertussis toxin–sensitive metabotropic receptor at rat dorsolateral septal nucleus neurons. Neuroscience 68: 423–434, 1995.
 542. Zhou, W., C. Flanagan, J. A. Ballesteros, K. Konvicka, J. S. Davidson, H. Weinstein, R. P. Millar, and S. C. Seaflon. A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin‐releasing hormone receptor. Mol. Pharmacol. 45: 165–170, 1994.
 543. Zhou, W., V. Rodic, S. Kitanovic, C. A. Flanagan, L. Chi, H. Weinstein, S. Maayani, R. P. Millar, and S. C. Seaflon. A locus of the gonadotropin‐releasing hormone receptor that differentiates agonist and antagonist binding sites. J. Biol. Chem. 270: 18853–18857, 1995.
 544. Zhu, O., A. Wang, and M. Ascoli. The lutropin/choriogonadotropin receptor is palmitoylated at intracellular cysteine residues. Mol. Endocrinol. 9: 141–150, 1995.
 545. Zhukovsky, E. A., and D. D. Oprian. Effect of carboxylic acid side chains on the absorption maximum of visual pigments. Science 246: 928–930, 1989.

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Article Title: G Protein‐Coupled Receptors and the G Protein Family
 

How to Cite

Alfredo Ulloa‐Aguirre, P. Michael Conn. G Protein‐Coupled Receptors and the G Protein Family. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 87-124. First published in print 1998. doi: 10.1002/cphy.cp070106