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Roles of Parathyroid Hormone and Parathyroid Hormone–Related Peptide in Calcium Metabolism and Bone Biology: Biological Actions and Receptors

Harald Jüppner, John T. Jr. Potts

10.1002/cphy.cp070317

Source: Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance

Originally published: 2000

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Parathyroid Hormone
1.1 Chemistry
1.2 Peripheral Metabolism
1.3 Actions in Kidney and Bone
2 Parathyroid Hormone‐Related Peptide
2.1 Chemistry: Role of the Amino‐terminal Portion in Calcium Metabolism
2.2 Biological Role in Bone Development
3 Receptors That Mediate Analogous and Distinct Molecular Actions of Parathyroid Hormone and Parathyroid Hormone–Related Peptide
3.1 The Parathyroid Hormone/Parathyroid Hormone–Related Peptide Receptor
3.2 The Type 2 Parathyroid Hormone Receptor
3.3 Additional Receptors
3.4 Structure‐Based Design of Analogues
4 Summary
Figure 1. Figure 1.

Parathyroid hormone (PTH), PTH‐related peptide (PTHrP), and a putative PTH‐like peptide from hypothalamus mediate their actions through the PTH/PTHrP receptor (solid line) and/or the PTH2 receptor (cross‐hatched line). Both receptors are closely related and belong to a distinct family of G protein–coupled receptors. In contrast to the PTH/PTHrP receptor, which is expressed in a large variety of fetal and adult tissues, the PTH2 receptor is expressed in only few organs and its biological functions are not established.
Figure 2. Figure 2.

Alignment of amino acid sequences of all known vertebrate parathyroid hormone (PTH) (left) and PTH‐related peptide species (right). Conserved residues are shaded; numbers indicate positions of amino acids in the mammalian peptide sequences.
Figure 3. Figure 3.

Alignment of the (1–34) amino acid sequences of all known vertebrate parathyroid hormone (PTH) and PTH‐related peptide (PTHrP) species. Amino acid residues conserved in both peptide families are shown in white boxes; amino acids identical to those residues found in either human PTH or human PTHrP are indicated by a dash; numbers indicate amino acid positions.
Figure 4. Figure 4.

Scheme of parathyroid hormone (PTH) secretion by the parathyroid gland and its interaction with the PTH/PTH‐related peptide receptor, the PTH2 receptor, and other putative receptors on target cells. Cleavage of intact hormone into amino‐terminal (N, hatched bar) and carboxyl‐terminal (C, solid bar) fragments by the parathyroid gland and by peripheral organs.
Figure 5. Figure 5.

Parathyroid hormone (PTH) triggers the translocation of preformed voltage‐dependent calcium channels from sites of intracellular sequestration to the apical membrane, which also undergoes rapid morphological changes that greatly increase its surface area. Intracellular free calcium rises significantly, and increased net transepithelial calcium transport occurs, mainly via enhanced Na+−Ca2+ exchange at the basolateral membrane, supported in turn by Na+−K+‐ATPase. Analogous events underlie PTH regulation of proximal tubular phosphate transport.
Figure 6. Figure 6.

Schematic representation of the intron–exon organization of the genes encoding parathyroid hormone (PTH) and PTH‐related peptide (PTHrP). Introns are represented by a solid line, coding and noncoding exons are shown (as boxes); numbers indicate amino acids, Met is the initiator methionine of the prepro‐sequences (cross‐hatched boxes), and +1 is the first residue of the mature peptide (solid boxes). UTR, untranslated region.
Figure 7. Figure 7.

Macroscopic findings in mice homozygous for parathyroid hormone–related peptide ablation of the (PTHrP) gene [From Karaplis et al. 129 with permission.]. A wild‐type fetus (left) and a PTHrP‐ablated littermate (right) were obtained by cesarean section at day 18.5 postcoitum and fixed in buffered formalin. The mutant exhibits a chondroskeletal phenotype characterized by a domed skull, short snout and mandible, protruding tongue, narrow thorax, and disproportionately short limbs.
Figure 8. Figure 8.

Schematic representation of the human parathyroid hormone (PTH)/PTH‐related peptide receptor and its gene organization. Upper panel: Amino acids shown in single‐letter code; amino terminus of the receptor at top; potential sites for N‐linked glycosylaton (three‐pronged branches); bars indicate boundaries between each of 14 coding exons; exon S encodes the putative signal peptide. Lower panel: Intron–exon structure; coding exons shown as boxes, with names and sizes (bp) indicated (n.d., not determined). The size of each intron is shown, and the approximate locations of two frequent polymorphisms are indicated.
Figure 9. Figure 9.

Amino acid sequence comparison of receptors for parathyroid hormone (PTH) and PTH‐related peptide (PTHrP). Strict consensus cladogram for aligning the known PTH/PTHrP receptors (PPR) and the human PTH2 receptor. Human corticotropin‐releasing factor receptor (CRFR) and mouse calcitonin receptor (CTR) were used as outgroups [From Bergwitz et al. 23 with permission.]
Figure 10. Figure 10.

Putative interaction between parathyroid hormone (PTH) or PTH‐related peptide (PTHrP) (gray) and the PTH/PTHrP receptor (black). The carboxyl‐terminus of the ligand appears to interact predominantly with the receptor's amino‐terminal extracellular domain, while the ligand's amino‐terminus interacts with the membrane‐spanning helices and the extracellular loops. Individual residues (black circles) in either PTH or PTHrP likely to interact directly with distinct portions of the PTH/PTHrP receptor are indicated (white) 20, 27, 164, 310.
Figure 11. Figure 11.

Regulation of chondrocyte proliferation and differentiation by parathyroid hormone‐related peptide (PTHrP) and Indian hedgehog (Ihh). PPR, PTH/PTHrP receptor; Ptc, Patched; Smo, Smoothened; Bmp, bone morphogenic protein; Col X, collagen X.
Figure 12. Figure 12.

Patients with Jansen's metaphyseal chondrodysplasia [259; photograph kindly provided by Drs. Kooh and Cole, Hospital for Sick Children, Toronto, Canada, and 57, 117].
Figure 13. Figure 13.

Upper panel: Schematic presentation of the human parathyroid hormone (PTH)/PTH‐related peptide receptor; two amino acid substitutions (H223 and T410) identified in patients with Jansen's metaphyseal chondrodysplasia are indicated 176, 236, 237.Lower panel: Conservation of the equivalent of residues H223 and T410 in all mammalian members of this family of G protein–coupled receptors; numbers indicate the position of the residue within the amino acid sequence of the respective receptors. GHRH, growth hormone–releasing hormone; VIP, vasoactive intestinal peptide; GIP, gastric inhibitory peptide; GLP, glucagon‐like peptide; PACAP, pituitary adenylate cyclase–activating peptide; CRE, corticotropin‐releasing factor.
Figure 14. Figure 14.

Functional properties of wild‐type (HKrk) and mutant parathyroid hormone (PTH)/PTH‐related peptide (PTHrP) receptors (HKrk‐H223R and HKrk‐T410P), which are transiently expressed in COS‐7 cells. [From Schipani et al. 237 with permission.] Basal cAMP accumulation of COS‐7 cells that express increasing (to maximal) concentrations of wild‐type or mutant PTH/PTHrP receptors (A), basal (B) and PTH‐stimulated (C) cAMP accumulation, and PTH‐stimulated inositol phosposphate accu mulation (D).
Figure 15. Figure 15.

Constitutive cAMP accumulation of COS‐7 cells expressing wild‐type (HKrk) or mutant (HKrk‐H223R and HKrk‐T410P) parathyroid hormone (PTH)/PTH‐related peptide (PTHrP) receptors is partially reversed by PTH or PTHrP analogues. [From Gardella et al. 87 with permission.] Effect of [D‐Trp12,Tyr34]bPTH(7–34)amide (solid triangle) [Leu11,D‐Trp12]PTHrP(7–34)amide (solid square), [Nle8,18,Tyr34]bPTH(7–34)amide (open triangle), or PTHrP(7–34)amide (open square) is shown with COS‐7 cells expressing the wild‐type PTH/PTHrP receptor (A), HKrk‐H223R (B), or HKrk‐T410P (C). D: Data generated with [Leu11,D‐Trp12]PTHrP(7–34)amide were replotted as percent of basal cAMP accumulation: wild‐type PTH/PTHrP receptor (solid circle), HKrk‐H223R (solid square), or HKrk‐T410P (open circle).
Figure 16. Figure 16.

Residues 5 and 23 in parathyroid hormone (PTH) and PTH‐related peptide (PTHrP) are important for the interaction with the PTH2 receptor: PTH (open square) binds to the PTH2 receptor with high affinity (IC50) and is an efficient activator of cAMP accumulation (EC50), while PTHrP (solid square) shows only poor binding and activation. Replacement of residue 5 and/or 23 in PTH by the corresponding PTHrP‐specific residue reduced binding affinity and/or activation efficacy, while the converse findings were made when PTH‐specific residues were introduced into PTHrP [From Gardella et al. 86 with permission.]


Figure 1.

Parathyroid hormone (PTH), PTH‐related peptide (PTHrP), and a putative PTH‐like peptide from hypothalamus mediate their actions through the PTH/PTHrP receptor (solid line) and/or the PTH2 receptor (cross‐hatched line). Both receptors are closely related and belong to a distinct family of G protein–coupled receptors. In contrast to the PTH/PTHrP receptor, which is expressed in a large variety of fetal and adult tissues, the PTH2 receptor is expressed in only few organs and its biological functions are not established.



Figure 2.

Alignment of amino acid sequences of all known vertebrate parathyroid hormone (PTH) (left) and PTH‐related peptide species (right). Conserved residues are shaded; numbers indicate positions of amino acids in the mammalian peptide sequences.



Figure 3.

Alignment of the (1–34) amino acid sequences of all known vertebrate parathyroid hormone (PTH) and PTH‐related peptide (PTHrP) species. Amino acid residues conserved in both peptide families are shown in white boxes; amino acids identical to those residues found in either human PTH or human PTHrP are indicated by a dash; numbers indicate amino acid positions.



Figure 4.

Scheme of parathyroid hormone (PTH) secretion by the parathyroid gland and its interaction with the PTH/PTH‐related peptide receptor, the PTH2 receptor, and other putative receptors on target cells. Cleavage of intact hormone into amino‐terminal (N, hatched bar) and carboxyl‐terminal (C, solid bar) fragments by the parathyroid gland and by peripheral organs.



Figure 5.

Parathyroid hormone (PTH) triggers the translocation of preformed voltage‐dependent calcium channels from sites of intracellular sequestration to the apical membrane, which also undergoes rapid morphological changes that greatly increase its surface area. Intracellular free calcium rises significantly, and increased net transepithelial calcium transport occurs, mainly via enhanced Na+−Ca2+ exchange at the basolateral membrane, supported in turn by Na+−K+‐ATPase. Analogous events underlie PTH regulation of proximal tubular phosphate transport.



Figure 6.

Schematic representation of the intron–exon organization of the genes encoding parathyroid hormone (PTH) and PTH‐related peptide (PTHrP). Introns are represented by a solid line, coding and noncoding exons are shown (as boxes); numbers indicate amino acids, Met is the initiator methionine of the prepro‐sequences (cross‐hatched boxes), and +1 is the first residue of the mature peptide (solid boxes). UTR, untranslated region.



Figure 7.

Macroscopic findings in mice homozygous for parathyroid hormone–related peptide ablation of the (PTHrP) gene [From Karaplis et al. 129 with permission.]. A wild‐type fetus (left) and a PTHrP‐ablated littermate (right) were obtained by cesarean section at day 18.5 postcoitum and fixed in buffered formalin. The mutant exhibits a chondroskeletal phenotype characterized by a domed skull, short snout and mandible, protruding tongue, narrow thorax, and disproportionately short limbs.



Figure 8.

Schematic representation of the human parathyroid hormone (PTH)/PTH‐related peptide receptor and its gene organization. Upper panel: Amino acids shown in single‐letter code; amino terminus of the receptor at top; potential sites for N‐linked glycosylaton (three‐pronged branches); bars indicate boundaries between each of 14 coding exons; exon S encodes the putative signal peptide. Lower panel: Intron–exon structure; coding exons shown as boxes, with names and sizes (bp) indicated (n.d., not determined). The size of each intron is shown, and the approximate locations of two frequent polymorphisms are indicated.



Figure 9.

Amino acid sequence comparison of receptors for parathyroid hormone (PTH) and PTH‐related peptide (PTHrP). Strict consensus cladogram for aligning the known PTH/PTHrP receptors (PPR) and the human PTH2 receptor. Human corticotropin‐releasing factor receptor (CRFR) and mouse calcitonin receptor (CTR) were used as outgroups [From Bergwitz et al. 23 with permission.]



Figure 10.

Putative interaction between parathyroid hormone (PTH) or PTH‐related peptide (PTHrP) (gray) and the PTH/PTHrP receptor (black). The carboxyl‐terminus of the ligand appears to interact predominantly with the receptor's amino‐terminal extracellular domain, while the ligand's amino‐terminus interacts with the membrane‐spanning helices and the extracellular loops. Individual residues (black circles) in either PTH or PTHrP likely to interact directly with distinct portions of the PTH/PTHrP receptor are indicated (white) 20, 27, 164, 310.



Figure 11.

Regulation of chondrocyte proliferation and differentiation by parathyroid hormone‐related peptide (PTHrP) and Indian hedgehog (Ihh). PPR, PTH/PTHrP receptor; Ptc, Patched; Smo, Smoothened; Bmp, bone morphogenic protein; Col X, collagen X.



Figure 12.

Patients with Jansen's metaphyseal chondrodysplasia [259; photograph kindly provided by Drs. Kooh and Cole, Hospital for Sick Children, Toronto, Canada, and 57, 117].



Figure 13.

Upper panel: Schematic presentation of the human parathyroid hormone (PTH)/PTH‐related peptide receptor; two amino acid substitutions (H223 and T410) identified in patients with Jansen's metaphyseal chondrodysplasia are indicated 176, 236, 237.Lower panel: Conservation of the equivalent of residues H223 and T410 in all mammalian members of this family of G protein–coupled receptors; numbers indicate the position of the residue within the amino acid sequence of the respective receptors. GHRH, growth hormone–releasing hormone; VIP, vasoactive intestinal peptide; GIP, gastric inhibitory peptide; GLP, glucagon‐like peptide; PACAP, pituitary adenylate cyclase–activating peptide; CRE, corticotropin‐releasing factor.



Figure 14.

Functional properties of wild‐type (HKrk) and mutant parathyroid hormone (PTH)/PTH‐related peptide (PTHrP) receptors (HKrk‐H223R and HKrk‐T410P), which are transiently expressed in COS‐7 cells. [From Schipani et al. 237 with permission.] Basal cAMP accumulation of COS‐7 cells that express increasing (to maximal) concentrations of wild‐type or mutant PTH/PTHrP receptors (A), basal (B) and PTH‐stimulated (C) cAMP accumulation, and PTH‐stimulated inositol phosposphate accu mulation (D).



Figure 15.

Constitutive cAMP accumulation of COS‐7 cells expressing wild‐type (HKrk) or mutant (HKrk‐H223R and HKrk‐T410P) parathyroid hormone (PTH)/PTH‐related peptide (PTHrP) receptors is partially reversed by PTH or PTHrP analogues. [From Gardella et al. 87 with permission.] Effect of [D‐Trp12,Tyr34]bPTH(7–34)amide (solid triangle) [Leu11,D‐Trp12]PTHrP(7–34)amide (solid square), [Nle8,18,Tyr34]bPTH(7–34)amide (open triangle), or PTHrP(7–34)amide (open square) is shown with COS‐7 cells expressing the wild‐type PTH/PTHrP receptor (A), HKrk‐H223R (B), or HKrk‐T410P (C). D: Data generated with [Leu11,D‐Trp12]PTHrP(7–34)amide were replotted as percent of basal cAMP accumulation: wild‐type PTH/PTHrP receptor (solid circle), HKrk‐H223R (solid square), or HKrk‐T410P (open circle).



Figure 16.

Residues 5 and 23 in parathyroid hormone (PTH) and PTH‐related peptide (PTHrP) are important for the interaction with the PTH2 receptor: PTH (open square) binds to the PTH2 receptor with high affinity (IC50) and is an efficient activator of cAMP accumulation (EC50), while PTHrP (solid square) shows only poor binding and activation. Replacement of residue 5 and/or 23 in PTH by the corresponding PTHrP‐specific residue reduced binding affinity and/or activation efficacy, while the converse findings were made when PTH‐specific residues were introduced into PTHrP [From Gardella et al. 86 with permission.]

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Article Title: Roles of Parathyroid Hormone and Parathyroid Hormone–Related Peptide in Calcium Metabolism and Bone Biology: Biological Actions and Receptors
 

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Harald Jüppner, John T. Jr. Potts. Roles of Parathyroid Hormone and Parathyroid Hormone–Related Peptide in Calcium Metabolism and Bone Biology: Biological Actions and Receptors. Compr Physiol 2011, Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance: 663-698. First published in print 2000. doi: 10.1002/cphy.cp070317