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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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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 [13,25]) 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 [25], 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 [17]. 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.
AMY1 receptor
C
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AMY2 receptor
C
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AMY3 receptor
C
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CGRP receptor
C
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AM1 receptor
C
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AM2 receptor
C
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CT receptor
C
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calcitonin receptor-like receptor
C
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Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. Br J Pharmacol. 176 Issue S1: S21-S141.
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 [4,10-11]. The major human CTR splice variant (hCT(a), which does not contain an insert) with RAMP1 (i.e. the AMY1(a) receptor) has a high affinity for CGRP [30], unlike hCT(a)-RAMP3 (i.e. AMY3(a) receptor) [4,10]. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent [23,26,28]. Emerging data suggests that AMY1 could be a second CGRP receptor [9].
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 [15]. CGRP-(8-37) acts as an antagonist of CGRP (pKi ~8) and inhibits some AM and AMY responses (pKi ~6-7). It is weak at CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency (pKi ~7), limiting its use [12]. Olcegepant shows the greatest selectivity between receptors but still has significant affinity for AMY1 receptors [30].
Gs 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 [29]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase [6].
[125I]-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible.