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Phospholipid‐Derived Second Messengers

John H. Exton

10.1002/cphy.cp070111

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 Inositol Phospholipid Hydrolysis
1.1 Functional Significance
1.2 Phosphoinositide Phospholipases as Targets of Hormones and Growth Factors
2 Phosphatidylinositol 3,4,5‐Trisphosphate Synthesis
2.1 Phosphatidylinositol 3‐Kinases as Targets of Hormones and Growth Factors
2.2 Role of Phosphatidylinositol 3‐Kinase in Cell Function
3 Phosphatidylcholine Hydrolysis
3.1 Phosphatidylcholine Hydrolysis by Phospholipase D and Its Functional Significance
3.2 Phospholipase D as a Target of Hormones and Growth Factors
3.3 Agonist‐Stimulated Phosphatidylcholine Hydrolysis by Phospholipase C
3.4 Agonist‐Stimulated Phosphatidylcholine Hydrolysis by Phospholipase A2
4 Sphingomyelin Hydrolysis and Its Functional Significance
5 Summary
Figure 1. Figure 1.

Mechanisms involved in physiological responses mediated by receptors linked through G proteins to phosphoinositide phospholipase C. G Prot, G protein; P Lipase, phospholipase C; PIP2, phosphatidylinositol 4,5–P2; IP3, inositol 1,4,5–P3; DAG, 1,2–diacylglycerol; CIF, putative Ca2+ influx factor; CRAC, Ca2+‐release‐activated Ca2+ channel; ER, endoplasmic reticulum; Mito, mitochondrion; Cam, calmodulin.
Figure 2. Figure 2.

Heterotrimeric G protein families. The four families of G protein α‐subunits are displayed in terms of their amino‐acid identity.

[Reproduced from Simon et al. 468, with permission.]
Figure 3. Figure 3.

Structural features of the β, γ, and δ isotypes of phosphoinositide phospholipase C. The conserved X and Y domains are believed to be involved in catalysis. PH, pleckstrin homology domain; SH2 and SH3, Src homology domains.
Figure 4. Figure 4.

Transmembrane‐spanning model of the bovine α1A‐adrenergic receptor. The seven transmembrane helices are defined on the basis of hydropathic analysis. Black residues are those common to the hamster α1B‐adrenergic receptor. Presumed glycosylation sites are marked with crosses.

[Reproduced from Schwinn et al. 465, with permission.]
Figure 5. Figure 5.

Mechanisms involved in activation/deactivation of heterotrimeric G proteins.
Figure 6. Figure 6.

Stimulation of phosphoinositide phospholipase β3 by G protein βγ‐subunits. Experimental conditions were as described in Blank et al. 405. βγ‐subunits were prepared from bovine brain or produced by recombinant means in Sf9 cells.

[From unpublished studies by J. L. Blank, J. A. Iniguez‐Luihi, N. Ueda, A. G. Gilman, and J. H. Exton.]
Figure 7. Figure 7.

Structure of the β receptor for platelet‐derived growth factor (PDGF). The figure presents schematically the binding domain for PDGF, the tyrosine kinase domains, the numbered phosphorylatable tyrosine residues, and the proteins that associate with these. Src, Src family members; Grb2, Shc, and Nck, adapter proteins with SH2 and SH3 domains; PI3K, the regulatory subunit of phosphati‐dylinositol 3‐kinase; GAP, the GTPase‐activating protein of Ras; PTP, a protein tyrosine phosphatase variously designated PTP1D, Syp, SHPTP2, or PTP2C; PLCγ, the γ isozyme of phosphoinositide phospholipase C.
Figure 8. Figure 8.

Pathways of synthesis of 3‐phosphorylated phosphoinositides. PI 3‐kin, phosphatidylinositol 3‐kinase; PI 4‐kin, phosphatidylinositol 4‐kinase; PI 3‐P 4‐kin, phosphatidylinositol 3‐P 4‐kinase; PI 4‐P 5‐kin; phosphatidylinositol 4‐P 5‐kinase.
Figure 9. Figure 9.

Effects of protein kinase C inhibitors (bis‐indoyl‐maleimide and Ro‐31–8220) on stimulation of phospholipase D by basic fibroblast growth factor (bFGF), bombesin (Bomb), and platelet‐derived growth factor (PDGF) in Swiss 3T3 cells. Phospholipase D activity was measured by the formation of radioactive phosphatidylbutanol (PtdBut) in cells previously labeled with [3H] myristic acid.

[Reproduced from Yeo and Exton 385, with permission.]
Figure 10. Figure 10.

Stimulation of HL60 phospholipase D by recombinant ADP‐ribosylation factor (ARF) (rARF) and ARF purified from bovine brain. Phospholipase D partially purified from HL60 membranes was assayed in the presence of GTPγS and the ARF forms.

[Data replotted from Brown et al. 33, with permission.]
Figure 11. Figure 11.

Effects of Rho GDP dissociation inhibitor (GDI) and Rho family members on activation of phospholipase D (PLD) by GTPγS in rat liver plasma membranes. Membranes were treated with GDI and then washed and incubated with or without GTPγS in the absence or presence of RhoA, Rac1, Cdc42, or ARF. Phospholipase D was assayed by transphosphatidylation with ethanol.

[Reproduced from Malcolm et al. 204, with permission.]
Figure 12. Figure 12.

Effects of C3 exoenzyme of Clostridium botulinum on the stimulation of phospholipase D in Rat1 fibroblasts by lysophosphatidic acid (LPA), endothelin‐1 (ET‐1), and phorbol myristate acetate (PMA). The exoenzyme was introduced into cells by scrape‐loading 24 h prior to labeling with [3H]myristic acid and 48 h prior to assay of phospholipase D by measurement of [3H]phosphatidylbutanol (PtdBut) formation.

[Reproduced from Malcolm et al. 203, with permission.]
Figure 13. Figure 13.

Mechanisms of regulation of cytosolic phospholipase A2 (cPLA2) by growth factors and agonists linked to G proteins (GProt). Tyr Kin tyrosine kinase; SOS, nucleotide exchange factor (GDP‐dissociation stimulator) for Ras; DAG, 1,2‐diacylglycerol; ER, endoplasmic reticulum; PLC, phospholipase C; PKC, protein kinase C; PIP2, phosphatidylinositol 4,5‐P2; IP3, inositol 1,4,5‐P3.
Figure 14. Figure 14.

Pathways of formation and breakdown of ceramide.


Figure 1.

Mechanisms involved in physiological responses mediated by receptors linked through G proteins to phosphoinositide phospholipase C. G Prot, G protein; P Lipase, phospholipase C; PIP2, phosphatidylinositol 4,5–P2; IP3, inositol 1,4,5–P3; DAG, 1,2–diacylglycerol; CIF, putative Ca2+ influx factor; CRAC, Ca2+‐release‐activated Ca2+ channel; ER, endoplasmic reticulum; Mito, mitochondrion; Cam, calmodulin.



Figure 2.

Heterotrimeric G protein families. The four families of G protein α‐subunits are displayed in terms of their amino‐acid identity.

[Reproduced from Simon et al. 468, with permission.]


Figure 3.

Structural features of the β, γ, and δ isotypes of phosphoinositide phospholipase C. The conserved X and Y domains are believed to be involved in catalysis. PH, pleckstrin homology domain; SH2 and SH3, Src homology domains.



Figure 4.

Transmembrane‐spanning model of the bovine α1A‐adrenergic receptor. The seven transmembrane helices are defined on the basis of hydropathic analysis. Black residues are those common to the hamster α1B‐adrenergic receptor. Presumed glycosylation sites are marked with crosses.

[Reproduced from Schwinn et al. 465, with permission.]


Figure 5.

Mechanisms involved in activation/deactivation of heterotrimeric G proteins.



Figure 6.

Stimulation of phosphoinositide phospholipase β3 by G protein βγ‐subunits. Experimental conditions were as described in Blank et al. 405. βγ‐subunits were prepared from bovine brain or produced by recombinant means in Sf9 cells.

[From unpublished studies by J. L. Blank, J. A. Iniguez‐Luihi, N. Ueda, A. G. Gilman, and J. H. Exton.]


Figure 7.

Structure of the β receptor for platelet‐derived growth factor (PDGF). The figure presents schematically the binding domain for PDGF, the tyrosine kinase domains, the numbered phosphorylatable tyrosine residues, and the proteins that associate with these. Src, Src family members; Grb2, Shc, and Nck, adapter proteins with SH2 and SH3 domains; PI3K, the regulatory subunit of phosphati‐dylinositol 3‐kinase; GAP, the GTPase‐activating protein of Ras; PTP, a protein tyrosine phosphatase variously designated PTP1D, Syp, SHPTP2, or PTP2C; PLCγ, the γ isozyme of phosphoinositide phospholipase C.



Figure 8.

Pathways of synthesis of 3‐phosphorylated phosphoinositides. PI 3‐kin, phosphatidylinositol 3‐kinase; PI 4‐kin, phosphatidylinositol 4‐kinase; PI 3‐P 4‐kin, phosphatidylinositol 3‐P 4‐kinase; PI 4‐P 5‐kin; phosphatidylinositol 4‐P 5‐kinase.



Figure 9.

Effects of protein kinase C inhibitors (bis‐indoyl‐maleimide and Ro‐31–8220) on stimulation of phospholipase D by basic fibroblast growth factor (bFGF), bombesin (Bomb), and platelet‐derived growth factor (PDGF) in Swiss 3T3 cells. Phospholipase D activity was measured by the formation of radioactive phosphatidylbutanol (PtdBut) in cells previously labeled with [3H] myristic acid.

[Reproduced from Yeo and Exton 385, with permission.]


Figure 10.

Stimulation of HL60 phospholipase D by recombinant ADP‐ribosylation factor (ARF) (rARF) and ARF purified from bovine brain. Phospholipase D partially purified from HL60 membranes was assayed in the presence of GTPγS and the ARF forms.

[Data replotted from Brown et al. 33, with permission.]


Figure 11.

Effects of Rho GDP dissociation inhibitor (GDI) and Rho family members on activation of phospholipase D (PLD) by GTPγS in rat liver plasma membranes. Membranes were treated with GDI and then washed and incubated with or without GTPγS in the absence or presence of RhoA, Rac1, Cdc42, or ARF. Phospholipase D was assayed by transphosphatidylation with ethanol.

[Reproduced from Malcolm et al. 204, with permission.]


Figure 12.

Effects of C3 exoenzyme of Clostridium botulinum on the stimulation of phospholipase D in Rat1 fibroblasts by lysophosphatidic acid (LPA), endothelin‐1 (ET‐1), and phorbol myristate acetate (PMA). The exoenzyme was introduced into cells by scrape‐loading 24 h prior to labeling with [3H]myristic acid and 48 h prior to assay of phospholipase D by measurement of [3H]phosphatidylbutanol (PtdBut) formation.

[Reproduced from Malcolm et al. 203, with permission.]


Figure 13.

Mechanisms of regulation of cytosolic phospholipase A2 (cPLA2) by growth factors and agonists linked to G proteins (GProt). Tyr Kin tyrosine kinase; SOS, nucleotide exchange factor (GDP‐dissociation stimulator) for Ras; DAG, 1,2‐diacylglycerol; ER, endoplasmic reticulum; PLC, phospholipase C; PKC, protein kinase C; PIP2, phosphatidylinositol 4,5‐P2; IP3, inositol 1,4,5‐P3.



Figure 14.

Pathways of formation and breakdown of ceramide.

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Article Title: Phospholipid‐Derived Second Messengers
 

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John H. Exton. Phospholipid‐Derived Second Messengers. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 255-291. First published in print 1998. doi: 10.1002/cphy.cp070111