The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [6]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (PTH, P01270) (84 amino acids), and PTHrP (PTHLH, P12272) (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36) (PTHLH, P12272)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (PTH2, Q96A98) (39 amino acids). [¹²⁵I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-G_s complex has been resolved by cryo-electron microscopy [10]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [2].

The parathyroid hormone type 1 receptor (PTHR) is the canonical GPCR for PTH and PTHrP. It is coupled to G_s and G_q and regulates the development of bone, heart, mammary glands and other tissues in response to PTHrP, and blood concentrations of calcium and phosphate ions, as well as vitamin D, in response to PTH. Another important action of the PTH/PTHR system is to stimulate bone formation when the hormone is intermittently administrated (daily injection).

Although PTH (PTH, P01270) is an agonist at human PTH2 receptors, it fails to activate the rodent orthologues. TIP39 (PTH2, Q96A98) is a weak antagonist at PTH1 receptors [9].

* Key recommended reading is highlighted with an asterisk

* Cheloha RW, Gellman SH, Vilardaga JP, Gardella TJ. (2015) PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol, 11 (12): 712-24. [PMID:26303600]

* Gardella TJ, Vilardaga JP. (2015) International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors-Family B G Protein-Coupled Receptors. Pharmacol Rev, 67 (2): 310-37. [PMID:25713287]

* Sutkeviciute I, Vilardaga JP. (2020) Structural insights into emergent signaling modes of G protein-coupled receptors. J Biol Chem, 295 (33): 11626-11642. [PMID:32571882]

* Vilardaga JP, Jean-Alphonse FG, Gardella TJ. (2014) Endosomal generation of cAMP in GPCR signaling. Nat Chem Biol, 10 (9): 700-6. [PMID:25271346]

1. Augustine M, Horwitz MJ. (2013) Parathyroid hormone and parathyroid hormone-related protein analogs as therapies for osteoporosis. Curr Osteoporos Rep, 11 (4): 400-6. [PMID:24078470]

2. Ehrenmann J, Schöppe J, Klenk C, Rappas M, Kummer L, Doré AS, Plückthun A. (2018) High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist. Nat Struct Mol Biol, 25 (12): 1086-1092. [PMID:30455434]

3. Gardella TJ, Luck MD, Fan MH, Lee C. (1996) Transmembrane residues of the parathyroid hormone (PTH)/PTH-related peptide receptor that specifically affect binding and signaling by agonist ligands. J Biol Chem, 271 (22): 12820-5. [PMID:8662729]

4. Gardella TJ, Luck MD, Jensen GS, Usdin TB, Jüppner H. (1996) Converting parathyroid hormone-related peptide (PTHrP) into a potent PTH-2 receptor agonist. J Biol Chem, 271 (33): 19888-93. [PMID:8702701]

5. Gardella TJ, Luck MD, Wilson AK, Keutmann HT, Nussbaum SR, Potts Jr JT, Kronenberg HM. (1995) Parathyroid hormone (PTH)-PTH-related peptide hybrid peptides reveal functional interactions between the 1-14 and 15-34 domains of the ligand. J Biol Chem, 270 (12): 6584-8. [PMID:7896796]

6. Gardella TJ, Vilardaga JP. (2015) International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors-Family B G Protein-Coupled Receptors. Pharmacol Rev, 67 (2): 310-37. [PMID:25713287]

7. Goold CP, Usdin TB, Hoare SR. (2001) Regions in rat and human parathyroid hormone (PTH) 2 receptors controlling receptor interaction with PTH and with antagonist ligands. J Pharmacol Exp Ther, 299 (2): 678-90. [PMID:11602681]

8. Hoare SR, Clark JA, Usdin TB. (2000) Molecular determinants of tuberoinfundibular peptide of 39 residues (TIP39) selectivity for the parathyroid hormone-2 (PTH2) receptor. N-terminal truncation of TIP39 reverses PTH2 receptor/PTH1 receptor binding selectivity. J Biol Chem, 275 (35): 27274-83. [PMID:10854439]

9. Jonsson KB, John MR, Gensure RC, Gardella TJ, Jüppner H. (2001) Tuberoinfundibular peptide 39 binds to the parathyroid hormone (PTH)/PTH-related peptide receptor, but functions as an antagonist. Endocrinology, 142 (2): 704-9. [PMID:11159842]

10. Zhao LH, Ma S, Sutkeviciute I, Shen DD, Zhou XE, de Waal PW, Li CY, Kang Y, Clark LJ, Jean-Alphonse FG et al.. (2019) Structure and dynamics of the active human parathyroid hormone receptor-1. Science, 364 (6436): 148-153. [PMID:30975883]

Subcommittee members: Jean-Pierre Vilardaga (Chairperson) E1357 Thomas E. Starzl Biomedical Science Tower 200 Lothrop Street, Pittsburgh, PA 15213 USA Alessandro Bisello E1358 Thomas E. Starzl Biomedical Science Tower Pittsburgh, PA 15261 USA Michael Chorev Harvard Medical School Lab for Translational Research, Bldg 600 One Kendall Sq Cambridge, MA 02139 USA Peter A. Friedman E1356 Biomedical Science Tower 200 Lothrop Street, Pittsburgh, PA 15261 USA Tom Gardella Massachusetts General Hospital Endocrine Unit, THR 1051 50 Blossom St Boston, MA 02114 USA Harald Jueppner Endocrine Unit Wellman 5 Massachusetts General Hospital Boston Massachusetts, 02114, USA T. John Martin St Vincent's Institute of Medical Research The University of Melbourne 9 Princes Street, Fitzroy 3065 Australia John Thomas Potts, Jr., M.D. Neuroendocrine Clinical Center Zero Emerson Place Suite 112 Boston, MA 02114-2217 USA Robert A. Nissenson Endocrine Research Unit (111 N) VA Medical Center and UCSF San Francisco, CA 94121 USA Caroline Silve INSERM U986 et Centre de reference des maladies rares du métabolisme du phosphate et du calcium Hopital Bicêtre Le Kremlin Bicêtre, France Ted B. Usdin (Past chairperson) Section on Fundamental Neuroscience, NIMH Bldg 35/Rm1B-215 35 Convent Drive MSC 3728 BETHESDA MD, 20892-3728, USA

Other contributors: Rebecca Hills (Past curator)