Calcitonin receptors: Introduction


The calcitonin peptide family comprises calcitonin, amylin, calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and AM2, also known as intermedin. The peptides range from 32 to 52 amino acids in length in humans [28]. Related peptides, such as calcitonin receptor-stimulating peptide exist in other species but will not be considered further here [40]. Each of these peptides has structural similarities and truncation of each peptide beyond the second cysteine residue generates antagonists. With the exception of some antagonists for CGRP receptors, such modified forms of the native peptides are the only pharmacological tools currently available for characterising these receptors. The receptor family for these peptides consists of two class B GPCRs, the calcitonin receptor (CT) and calcitonin receptor-like receptor (commonly abbreviated as CLR) for which pharmacological specificity is dictated by additional proteins, known as receptor activity-modifying proteins (RAMPs). These are integral parts of the receptor complex [28].


Calcitonin is a 32 amino acid peptide, involved in bone homeostasis [20]. In humans, calcitonin is derived from the parafollicular (C cells) of the thyroid. Salmon calcitonin 8-32 (sCT8-32) is a commonly used antagonist of calcitonin receptors. Interestingly, salmon calcitonin is considerably more potent than human calcitonin.


Amylin (formerly known as islet amyloid polypeptide or diabetes associated peptide) is a 37 amino acid peptide first purified from amyloid deposits in the pancreatic islets of type 2 diabetic patients [14]. It is a product of the islet β-cell, along with insulin and probably has a hormonal role in the regulation of nutrient intake [25]. Human amylin has a tendency to aggregate and form fibrils and this is associated with islet death, although it is unclear whether early protofibrils or the amyloid deposits themselves are responsible [25]. Therefore rat amylin, which does not aggregate, is more commonly used as a pharmacological tool. This property of rodent amylin was exploited in the development of pramlintide (SymlinTM). This is a modified, non fibrillogenic form of human amylin which is used to treat diabetes.

sCT8-32 is also an antagonist of amylin receptors. rAMY8-37 has been reported to antagonise various responses to amylin in vivo and in isolated tissue preparations [15,53,65-66]. However, full concentration analyses have rarely been performed with this antagonist. In cell culture studies with transfected AMY1(a) and AMY3(a) receptors, rAmy8-37 was very weak with pKB values of around 5.8 [26]. AC187, reportedly a selective amylin antagonist [70], displays only modest (~10-fold) discrimination between CT and AMY1(a) receptors in transfected cells [26]. Similar observations were made with AC413, like AC187, a modified form of sCT8-32 [26].

Calcitonin gene-related peptide

CGRP is an alternative product of the calcitonin gene and was first described in 1982 [2]. α-CGRP is generated by alternate splicing of the calcitonin gene. β-CGRP, on the other hand, is a product of a second gene which does not produce calcitonin. The amino acid sequences of α- and β-CGRP are very similar, differing by only 3 amino acids in humans. Generally, α- and β-CGRP have very similar biological activities.

CGRP is a potent vasodilator with multiple reported pharmacological activities (summarised in [8-9,57]). α-CGRP is broadly distributed throughout the central and peripheral nervous systems of vertebrates. α-CGRP is found in the dorsal horn of the spinal cord, the perivascular neural network of blood vessels and in Aδ and C-fibre sensory and motor nerves. Whilst the distributions of α-CGRP and β-CGRP predominantly overlap, β-CGRP is the major isoform found in the enteric nervous system [50,59].

CGRP8-37 is the peptide antagonist of CGRP [12]. There has been much interest in developing small molecule CGRP receptor antagonists for the treatment of migraine. The best characterized of these pharmacologically are BIBN4096BS [19,27,45] and MK-0974; the latter is orally bioavailable [48-49,58].


AM is the largest peptide in the calcitonin peptide family, being 52 amino acids in length in humans and 50 in rodents and was discovered in 1993 [41]. AM is a product of endothelial cells and like CGRP is a potent vasodilator [33]. Knockout mouse models of the AM gene point to an important role for this peptide in the development of the blood and lymphatic vasculature (see below). The best AM antagonist available is AM22-52, although it has a pA2 of only around 7 in cell culture systems and is only of limited use in vivo [29,54]. AM2, also known as intermedin, has recently been added to the list of members of the calcitonin family of peptides [35,56,63]. The study of this peptide is still in its infancy and it is not clear whether it has its own cognate receptor or whether most of its pharmacological actions can be attributed to its affinity at CGRP and AM receptors especially the AM2 receptor [26,35,56,63]. An AM2/intermedin antagonist is the 17-47 fragment of the peptide [56].

Receptor types

CT receptors are class B GPCRs, a family which includes receptors such as the secretin receptor, parathyroid hormone receptor and calcitonin receptor-like receptor. These receptors share conserved cysteines in their extracellular N-termini of ~100-160 amino acids. There is a general mechanism of binding to these receptors, whereby the C-terminal region binds to the extracellular N-terminus of the receptor whereas the N-terminus of the peptide interacts with the juxtamembrane region of the receptor [34].

Whilst the receptor for calcitonin is a conventional class B GPCR, the receptors for CGRP, AM and amylin require additional proteins, called the receptor activity modifying proteins (RAMPs) [32,47]. There are three RAMPs in mammals; they interact with the CT receptor to convert it to receptors for amylin. For CGRP and AM, the related calcitonin receptor-like receptor interacts with RAMP1 to give a CGRP receptor and RAMP2 or 3 to give AM receptors. Calcitonin receptor-like receptor by itself will bind no known endogenous ligand. Structurally, each RAMP has a short intracellular C-terminus with a single transmembrane spanning domain and an N-terminus of ~100 amino acids. The interaction of the N-terminus of the RAMP with the N-terminus of the GPCR determines the specific pharmacology of each receptor complex [32]. Our understanding of the mode of action of RAMPs has been greatly helped by crystal structures showing the complex of the N-termini of CLR and RAMP1, by themselves and with the non-peptide antagonists BIBN4096BS and MK-0974 bound [3]. A CLR/RAMP2 crystal structure is also available [42]. To these may be added structures of the N-termini of CLR/RAMP1 and RAMP2 with modified forms of CGRP27-37 and AM37-52 bound [7]

The first CT receptor, a porcine receptor, was cloned in 1991 [44], followed closely by the human homolog of this receptor, now known as hCT(b) [23,54]. A CT receptor with identical sequence, aside from 16 amino acids fewer in the first intracellular loop as a result of alternative splicing, is known as hCT(a). Such CT receptors have previously been known as CTR1 and CTR2 or insert positive (CTRI1+) or negative (CTRI1-) respectively and consequently the nomenclature can be confusing. There are other splice variants in humans, such as that which lacks the first 47 amino acids in the N-terminus [1]. They are reviewed in Sexton et al. [20] and Purdue et al. [55]. hCT(a) is the most widely distributed receptor and the most extensively studied. CT(a) is also found in rodents. the insert positive rodent receptor (CTECL1+/CTe2+) has a 37 amino acid insert in the first extracellular loop. CT receptor variants differ in their binding properties, ability to couple to signal transduction pathways and some have dominant negative activity. The physiological significance of the variants is generally unknown. A further human calcitonin receptor variant has a T to C base mutation, encoding a leucine447 to proline change. The substitution has no apparent effect on ligand binding or receptor function in vitro but the polymorphism is associated with decreased fracture risk in post-menopausal women [46,51,62,69].

Amylin receptors have always been closely associated with CT receptors. This can be explained because amylin receptors are multimeric complexes, formed by CT receptor interaction with RAMPs. The CT receptor interacts with the three RAMPs, generating multiple subtypes of amylin receptor (AMY1-3) [13,54,64]. The amylin receptor subtypes are pharmacologically distinct and AMY1(a) and AMY3(a) receptors are the best characterised. These receptors bind amylin with high affinity but AMY1(a) receptors also interact with CGRP with high affinity and it has been suggested that CGRP can activate these receptors physiologically [68]. On the other hand, AMY3(a) receptors show less preference for this peptide [26]. CT(b) also interacts with RAMPs to generate subtly different pharmacological phenotypes [64]. Pharmacological characterisation of rat AMY1(a) and AMY3(a) receptors shows that there are some differences between species [5].

CGRP receptors are complexes between calcitonin receptor-like receptor and RAMP1 [47], having high affinity for CGRP (~0.1-1nM) and around a 10-fold lower affinity for AM and the antagonist CGRP8-37 [54]. There are high affinity, non-peptide antagonists of CGRP receptors [3,49,58], the best characterised of which is BIBN4096BS [19]. CGRP8-37 is not a selective CGRP receptor antagonist as it has significant affinity at other CGRP-responsive receptors. BIBN4096BS is only selective for CGRP receptors over other CGRP-responsive receptors at low concentrations. This compound has a sub-nanomolar affinity for primate CGRP receptors but binds with around 100-fold lower affinity to CGRP receptors from other species. Species and pharmacological selectivity is due to a tryptophan at position 74 in primate RAMP1 [32,45]. As noted above, the AMY1 receptor may also be an important CGRP receptor.

There are two AM receptors; AM1 formed by calcitonin receptor-like receptor/RAMP2 and AM2 formed by calcitonin receptor-like receptor/RAMP3. They show high affinity for AM and modest affinity for the antagonist AM22-52. AM1 receptors appear to have ~100-fold selectivity for AM over CGRP with the AM2 receptor apparently exhibiting less discrimination (~50-fold), depending on species [29,47,54]. The peptide AM2 has a potency similar to that of AM at the AM2 receptor [35]. RAMP3 has a PDZ domain in its C-terminus, so that in the appropriate circumstances the AM2 receptor recycles after internalisation whereas the AM1 receptor does not [6].

Functional role of individual receptors

The calcitonin peptide family is involved in numerous physiological and pharmacological activities. This is associated with significant complexity at the receptor level, encompassing splice variants and RAMPs, generating unique challenges for delineating the role of individual receptors. As such, the presence of mRNA for an individual receptor component is virtually meaningless without consideration for the whole receptor complex. Furthermore, there may be a lack of correlation between mRNA and protein [30]. Thus, receptor mRNA will not be discussed in this section as it is insufficiently informative.

For calcitonin, where there is only one gene encoding a specific CT receptor, the situation indicating the involvement of this receptor is relatively straightforward. The most well-known action of calcitonin is the regulation of bone metabolism, in particular the inhibition of bone resorption by osteoclasts [11]. Global deletion of exons 6 and 7 of calcr results in embryonic death prior to initiation of skeletogenesis. Counterintuitively, calcr+/- mice have a high bone mass phenotype due to increased bone formation [16]. A more recent, viable global CT receptor-deletion mouse model, generated using the Cre-loxP system (>94% calcitonin receptor deletion), sought to clarify the role of calcitonin in the regulation of bone [17]. Here, mice displayed mildly increased bone formation under normal conditions but when challenged, in calcitriol (1,25(OH)2D3)-induced hypercalcaemia, serum total calcium was greatly increased in the knockout mice. Together with data on knockout of calca (the calcitonin/CGRP gene), the data are supportive of a role for calcitonin and its receptor in the formation and resorption aspects of bone metabolism under physiological conditions. More challenging is the definition of the role of CT receptor splice variants.

There is general support for CT receptor/RAMP complexes as physiological receptors for amylin [25]. However, due to the lack of selective pharmacological tools, significant complexity in this system and lack of specific RAMP antibodies, it is difficult to assign amylin function to individual receptor subtypes. Furthermore, in addition to exhibiting changes in glucose and insulin [22], amylin-deficient mice display low bone mass due to increased bone resorption [16]. However, as described above, calcr deficient mice show greater bone formation. This suggests that the CT receptor does not mediate the actions of amylin on bone and that other receptors for this peptide may mediate this effect.

For CGRP, we are fortunate to have some selective tools. In particular, the potent CGRP antagonist BIBN4096BS is particularly useful. This became available in 2000 and has not been as widely used as CGRP8-37. Nevertheless, in the pig, BIBN4096BS did not affect heart rate, blood pressure, systemic vascular conductance or cardiac output [38-39]. Similar observations have been made in the rat [4]. When given to normal, healthy volunteers, BIBN4096BS did not affect cerebral or systemic hemodynamics suggesting that, under resting conditions, CGRP has only a minor role in the regulation of vascular tone [52]. Based on the effects of this antagonist, the CGRP receptor may not be a major physiological regulator of blood pressure or heart rate in humans, rats or pigs. On the other hand, deletion of RAMP1 caused an increase in blood pressure with no associated change in heart rate. Although RAMP1 has other functions, in addition to forming CGRP receptors, inhibition of CGRP receptor function is the simplest explanation for this result [55]. There may be changes in CGRP and its receptors during hypertension [57,61].

There is now a substantial body of work demonstrating the importance of AM in angiogenesis and lymphangiogenesis. AM-/- mice die in utero with abnormalities to their cardiovascular systems [10,60]. Furthermore, the phenotype of these and calcrl-/- and ramp2-/- mice may be explained by abnormalities in blood and lymphatic vasculature [21,36]. These genetic models support the AM system, in particular via AM1 receptors, as a key angiogenic pathway [37]. Otherwise, due to similar issues to amylin receptors, it is generally unknown which AM receptor is responsible for the varied physiological or pathophysiological activities of this peptide.

Nomenclature considerations

The unique composition of calcitonin-family receptors and the recent discovery of AM2/intermedin creates challenges for the nomenclature of these receptors. Furthermore, there has been a long-standing debate over the molecular nature of CGRP2 receptors.

The calcitonin receptor-like receptor/RAMP1 complex has been known as the CGRP1 receptor, based on the observation that there are situations where CGRP could not be blocked with high affinity by antagonists such as CGRP8-37. Linear agonists such as [Cys2,7 acetamidomethyl]-CGRP showed some selectivity for these tissues [18,54]. Receptors which responded to CGRP but were weakly antagonised by CGRP8-37 were known as CGRP2 receptors. It now seems likely that this CGRP2 receptor phenotype is due to expression of the AM2 and AMY1(a) receptors [24,26,43] that show appreciable affinity for CGRP. The term "CGRP2 receptor" is not currently recognised by IUPHAR [31]. None-the-less, it should be born in mind that CGRP can potently activate the AMY1 receptor [67-68] where it may act as a physiologically relevant agonist. On this basis, it should not be assumed that all CGRP-mediated responses occur through the calcitonin receptor-like receptor/RAMP1 CGRP receptor.

A second important matter is that the peptide known as AM2 is so named for other reasons and not because of its activity at the AM2 receptor [35,56,63].

There is no officially approved abbreviation of calcitonin receptor-like receptor, although CLR is widely used and at the most recent of the international meetings on CGRP, calcitonin, amylin and adrenomedullin (8th International meeting, Switzerland, 2014), the participants agreed that this should continue to be the preferred abbreviation.


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