Overview: Calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on CGRPs, AM, AMY, and CT receptors, see Poyner et al., 2002) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL (which codes for the calcitonin receptor-like receptor, CL receptor, previously known as CRLR), whose function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying protein). RAMPs are single TM domain proteins of ca. 130 amino acid, identified as a family of three members; RAMP1 (ENSG00000132329), RAMP2 (ENSG00000131477) and RAMP3 (ENSG00000122679). There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor (see Poyner et al., 2002) The endogenous agonists are the peptides CT, CGRP (also known as CGRP-I), CGRP (also known as CGRP-II), AMY (also known as islet-amyloid polypeptide, diabetes-associated polypeptide) and AM. There are species differences in peptide sequences, particularly for the CTs. AM2/Intermedin (AM2/IMD) can also activate CGRP1, AM1, AM2 and AMY1 receptors, albeit less potently than the cognate agonists (Ogoshi et al., 2003; Roh et al., 2004; Hay et al., 2005). CT receptor-stimulating peptide (CRSP) is another member of the family with selectivity for the CT receptor; it has not been found in humans (Katafuchi et al., 2003). BIBN4096BS is the most selective antagonist available, having a high selectivity for CGRP1 receptors, with a particular preference for those of primate origin. CGRP-(8–37) acts as an antagonist of CGRP (pK_i 6.5–8.0) and inhibits some AM and AMY responses (7.0). It is inactive at CT receptors. Salmon calcitonin-(8–32) is an antagonist at both amylin and CT receptors. AC187, a salmon CT analogue, is also an antagonist at amylin and CT receptors. Human AM-(22–52) has some selectivity towards AM receptors, but with modest potency, limiting its use.

Table 1.

Full table

The agonists described represent the best available but their selectivity is limited. AM has appreciable affinity for CGRP receptors and some of its effects can be antagonised by CGRP-(8–37). CGRP can show significant cross-reactivity at amylin receptors and some AM receptors. Responsiveness to human CT can be affected by splice variation (at the rat C1b receptor it is very weak, Houssami et al., 1994). Particularly for AMY receptors, relative potency can vary with the type and level of RAMP present and can be influenced by other factors such as G-proteins (Tilakaratne et al., 2000).

G_s is a prominent route for effector coupling but other pathways (e.g. Ca²⁺ and nitric oxide) and G-proteins can be activated. The coupling can be affected by splice variants of the CT receptor (e.g. the 490 amino-acid form of the human receptor, CT(b), does not cause an increase in intracellular Ca²⁺ and might have low efficacy in generating cAMP).

There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ENSG00000126522) is important for the coupling of the CL receptor to adenylyl cyclase (Evans et al., 2000). When co-expressed with RAMP2, the CL receptor produces an AM receptor (AM1). RAMP3 interacts with the CL receptor to give another receptor that is responsive to AM (AM2, Fraser et al., 1999). There is some evidence that these AM receptors are pharmacologically distinct (Hay et al., 2003). Transfection of hCT(a) with any RAMP can give a receptor with a high affinity for both salmon CT and AMY and varying affinity for different antagonists (Christopoulos et al., 1999; Hay et al., 2005, 2006). hCT(a)—RAMP1 has a high affinity for CGRP, unlike hCT(a)—RAMP3 (Christopoulos et al., 1999; Hay et al., 2005). However, AMY receptor phenotype is RAMP-type- and cell-line-dependent (Tilakaratne et al., 2000).

[¹²⁵I]-Salmon calcitonin is the most common radioligand for calcitonin receptors but it has high affinity for amylin receptors and is also poorly reversible. [¹²⁵I]-Tyr⁰-CGRP is widely used as a radioligand for CGRP receptors.

CGRP₁ and CGRP₂ subtypes have been proposed on the basis of the action of the agonists [Cys(ACM)^2,7]CGRP or [Cys(Et)^2,7]CGRP (putative CGRP₂-selective agents) and antagonist CGRP-(8–37) (CGRP₁-selective, pki 7.0–8.0, Juaneda et al., 2000). CL/RAMP1 represents the CGRP₁ subtype previously described in native tissues and cell lines (Aiyar et al., 1996; McLatchie et al., 1998). There is not yet a clear molecular correlate for the CGRP₂ receptor, although in some cases it may represent CGRP acting via AM2 or amylin receptors.