This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [15,27]) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 130 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [27], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin (CALCA, P01258), α-CGRP (CALCA, P06881) (formerly known as CGRP-I), β-CGRP (CALCB, P10092) (formerly known as CGRP-II), amylin (IAPP, P10997) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin (ADM, P35318) and adrenomedullin 2/intermedin (ADM2, Q7Z4H4). There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CT receptor but it is not expressed in humans [19]. Olcegepant (also known as BIBN4096BS, pKi~10.5) and telcagepant (also known as MK0974, pKi~9) are the most selective antagonists available, showing selectivity for CGRP receptors, with a particular preference for those of primate origin. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin.

It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP-coupled CTR as well as CTR alone. This means that although in binding assays human calcitonin (CALCA, P01258) has low affinity for ¹²⁵I-AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists [5,12-13]. The major human CTR splice variant (hCT_(a), which does not contain an insert) with RAMP1 (i.e. the AMY_1(a) receptor) has a high affinity for CGRP [33], unlike hCT_(a)-RAMP3 (i.e. AMY_3(a) receptor) [5,12]. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent [25,28,31]. Emerging data suggests that AMY₁ could be a second CGRP receptor [11].

The ligands described have limited selectivity. Adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM₂ receptors. Adrenomedullin 2/intermedin also has high affinity for the AM₂ receptor [17]. CGRP-(8-37) acts as an antagonist of CGRP (pK_i ~8) and inhibits some AM and AMY responses (pK_i ~6-7). It is weak at CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency (pK_i ~7), limiting its use [14]. Olcegepant shows the greatest selectivity between receptors but still has significant affinity for AMY₁ receptors [33].

G_s is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca²⁺, ERK, Akt), and G proteins can be activated [32]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase [7].

[¹²⁵I]-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible.

* Key recommended reading is highlighted with an asterisk

Booe JM, Walker CS, Barwell J, Kuteyi G, Simms J, Jamaluddin MA, Warner ML, Bill RM, Harris PW, Brimble MA et al.. (2015) Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor. Mol. Cell, 58 (6): 1040-52. [PMID:25982113]

* Hay DL, Garelja ML, Poyner DR, Walker CS. (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br. J. Pharmacol., 175 (1): 3-17. [PMID:29059473]

* Hay DL, Pioszak AA. (2016) Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu. Rev. Pharmacol. Toxicol., 56: 469-87. [PMID:26514202]

* Kato J, Kitamura K. (2015) Bench-to-bedside pharmacology of adrenomedullin. Eur. J. Pharmacol., 764: 140-8. [PMID:26144371]

* Russell FA, King R, Smillie SJ, Kodji X, Brain SD. (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev., 94 (4): 1099-142. [PMID:25287861]

* Russo AF. (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu. Rev. Pharmacol. Toxicol., 55: 533-52. [PMID:25340934]

1. Aiyar N, Disa J, Pullen M, Nambi P. (2001) Receptor activity modifying proteins interaction with human and porcine calcitonin receptor-like receptor (CRLR) in HEK-293 cells. Mol. Cell. Biochem., 224 (1-2): 123-33. [PMID:11693189]

2. Albrandt K, Brady EM, Moore CX, Mull E, Sierzega ME, Beaumont K. (1995) Molecular cloning and functional expression of a third isoform of the human calcitonin receptor and partial characterization of the calcitonin receptor gene. Endocrinology, 136 (12): 5377-84. [PMID:7588285]

3. Armour SL, Foord S, Kenakin T, Chen WJ. (1999) Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor. J Pharmacol Toxicol Methods, 42 (4): 217-24. [PMID:11033437]

4. Avgoustou P. et al.. (2020) Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor. ACS Pharmacol. Transl. Sci., [Epub ahead of print]. DOI: 10.1021/acsptsci.0c00032

5. Christopoulos G, Perry KJ, Morfis M, Tilakaratne N, Gao Y, Fraser NJ, Main MJ, Foord SM, Sexton PM. (1999) Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Mol. Pharmacol., 56 (1): 235-42. [PMID:10385705]

6. Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br. J. Pharmacol., 129 (3): 420-3. [PMID:10711339]

7. Evans BN, Rosenblatt MI, Mnayer LO, Oliver KR, Dickerson IM. (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J. Biol. Chem., 275 (40): 31438-43. [PMID:10903324]

8. Fraser NJ, Wise A, Brown J, McLatchie LM, Main MJ, Foord SM. (1999) The amino terminus of receptor activity modifying proteins is a critical determinant of glycosylation state and ligand binding of calcitonin receptor-like receptor. Mol Pharmacol., 55: 1054-1059. [PMID:10347248]

9. Gingell JJ, Burns ER, Hay DL. (2014) Activity of pramlintide, rat and human amylin but not Aβ1-42 at human amylin receptors. Endocrinology, 155 (1): 21-6. [PMID:24169554]

10. Gydesen S, Andreassen KV, Hjuler ST, Christensen JM, Karsdal MA, Henriksen K. (2016) KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight. Am. J. Physiol. Endocrinol. Metab., 310 (10): E821-7. [PMID:26908506]

11. Hay DL. (2019) CGRP Receptor Biology: Is There More Than One Receptor?. Handb Exp Pharmacol, 255: 13-22. [PMID:29797087]

12. Hay DL, Christopoulos G, Christopoulos A, Poyner DR, Sexton PM. (2005) Pharmacological discrimination of calcitonin receptor: receptor activity-modifying protein complexes. Mol. Pharmacol., 67 (5): 1655-65. [PMID:15692146]

13. Hay DL, Christopoulos G, Christopoulos A, Sexton PM. (2006) Determinants of 1-piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) affinity for calcitonin gene-related peptide and amylin receptors--the role of receptor activity modifying protein 1. Mol Pharmacol, 70: 1984-1991. [PMID:16959943]

14. Hay DL, Howitt SG, Conner AC, Schindler M, Smith DM, Poyner DR. (2003) CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS. Br. J. Pharmacol., 140 (3): 477-86. [PMID:12970090]

15. Hay DL, Poyner DR, Quirion R, International Union of Pharmacology. (2008) International Union of Pharmacology. LXIX. Status of the calcitonin gene-related peptide subtype 2 receptor. Pharmacol. Rev., 60 (2): 143-5. [PMID:18552275]

16. Hilton JM, Dowton M, Houssami S, Sexton PM. (2000) Identification of key components in the irreversibility of salmon calcitonin binding to calcitonin receptors. J. Endocrinol., 166 (1): 213-26. [PMID:10856900]

17. Hong Y, Hay DL, Quirion R, Poyner DR. (2012) The pharmacology of adrenomedullin 2/intermedin. Br. J. Pharmacol., 166 (1): 110-20. [PMID:21658025]

18. Joshi P, Anderson C, Binch H, Hadida S, Yoo S, Bergeron D, Decker C, terHaar E, Moore J, Garcia-Guzman M et al.. (2014) Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists. Bioorg. Med. Chem. Lett., 24 (3): 845-9. [PMID:24405707]

19. Katafuchi T, Kikumoto K, Hamano K, Kangawa K, Matsuo H, Minamino N. (2003) Calcitonin receptor-stimulating peptide, a new member of the calcitonin gene-related peptide family. Its isolation from porcine brain, structure, tissue distribution, and biological activity. J. Biol. Chem., 278 (14): 12046-54. [PMID:12556539]

20. Kuwasako K, Cao YN, Nagoshi Y, Tsuruda T, Kitamura K, Eto T. (2004) Characterization of the human calcitonin gene-related peptide receptor subtypes associated with receptor activity-modifying proteins. Mol. Pharmacol., 65 (1): 207-13. [PMID:14722252]

21. Kuwasako K, Kitamura K, Nagoshi Y, Eto T. (2003) Novel calcitonin-(8-32)-sensitive adrenomedullin receptors derived from co-expression of calcitonin receptor with receptor activity-modifying proteins. Biochem. Biophys. Res. Commun., 301 (2): 460-4. [PMID:12565884]

22. Leuthauser K, Gujer R, Aldecoa A, McKinney RA, Muff R, Fischer JA, Born W. (2000) Receptor-activity-modifying protein 1 forms heterodimers with two G-protein-coupled receptors to define ligand recognition. Biochem J., 351: 347-351. [PMID:11023820]

23. Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA. (2002) Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. J. Biol. Chem., 277 (16): 14294-8. [PMID:11847213]

24. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature, 393 (6683): 333-9. [PMID:9620797]

25. Morfis M, Tilakaratne N, Furness SG, Christopoulos G, Werry TD, Christopoulos A, Sexton PM. (2008) Receptor activity-modifying proteins differentially modulate the G protein-coupling efficiency of amylin receptors. Endocrinology, 149 (11): 5423-31. [PMID:18599553]

26. Muff R, Bühlmann N, Fischer JA, Born W. (1999) An amylin receptor is revealed following co-transfection of a calcitonin receptor with receptor activity modifying proteins-1 or -3. Endocrinology, 140 (6): 2924-7. [PMID:10342886]

27. Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM. (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol. Rev., 54 (2): 233-46. [PMID:12037140]

28. Qi T, Dong M, Watkins HA, Wootten D, Miller LJ, Hay DL. (2013) Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Δ(1-47)hCT((a)) function. Br. J. Pharmacol., 168 (3): 644-57. [PMID:22946511]

29. Salvatore CA, Hershey JC, Corcoran HA, Fay JF, Johnston VK, Moore EL, Mosser SD, Burgey CS, Paone DV, Shaw AW et al.. (2008) Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J. Pharmacol. Exp. Ther., 324 (2): 416-21. [PMID:18039958]

30. Sonne N, Larsen AT, Andreassen KV, Karsdal MA, Henriksen K. (2020) The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, Induces an Equally Potent Weight Loss Across a Broad Dose Range While Higher Doses May Further Improve Insulin Action. J. Pharmacol. Exp. Ther., 373 (1): 92-102. [PMID:31992608]

31. Tilakaratne N, Christopoulos G, Zumpe ET, Foord SM, Sexton PM. (2000) Amylin receptor phenotypes derived from human calcitonin receptor/RAMP coexpression exhibit pharmacological differences dependent on receptor isoform and host cell environment. J. Pharmacol. Exp. Ther., 294 (1): 61-72. [PMID:10871296]

32. Walker CS, Conner AC, Poyner DR, Hay DL. (2010) Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol. Sci., 31 (10): 476-83. [PMID:20633935]

33. Walker CS, Eftekhari S, Bower RL, Wilderman A, Insel PA, Edvinsson L, Waldvogel HJ, Jamaluddin MA, Russo AF, Hay DL. (2015) A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol, 2 (6): 595-608. [PMID:26125036]

Subcommittee members: Debbie Hay (Chairperson) Maurice Wilkins Centre and Centre for Brain Research Room 4022, School of Biological Sciences Thomas Building 3A Symonds Street University of Auckland Private bag 92019 Auckland 1142 New Zealand Christopher S. Walker School of Biological Sciences Thomas Building 3A Symonds Street University of Auckland Private bag 92019 Auckland 1142 New Zealand

Other contributors: David R. Poyner (Past chairperson) School of Life and Health Sciences Aston University Aston Triangle Birmingham B4 7ET UK