General

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

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 (sCT_8-32) is a commonly used antagonist of calcitonin receptors. Interestingly, salmon calcitonin is considerably more potent than human calcitonin.

Amylin

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 (Symlin^TM). This is a modified, non fibrillogenic form of human amylin which is used to treat diabetes.

sCT_8-32 is also an antagonist of amylin receptors. rAMY_8-37 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 AMY_1(a) and AMY_3(a) receptors, rAmy_8-37 was very weak with pK_B values of around 5.8 [26]. AC187, reportedly a selective amylin antagonist [70], displays only modest (~10-fold) discrimination between CT and AMY_1(a) receptors in transfected cells [26]. Similar observations were made with AC413, like AC187, a modified form of sCT_8-32 [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].

CGRP_8-37 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].

Adrenomedullins

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 AM_22-52, 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

General
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 CGRP_27-37 and AM_37-52 bound [7]

CT
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 (CTR_I1⁺) or negative (CTR_I1^-) 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 (CT_ECL1+/CT_e2+) 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].

AMY_1-3
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 (AMY_1-3) [13,54,64]. The amylin receptor subtypes are pharmacologically distinct and AMY_1(a) and AMY_3(a) receptors are the best characterised. These receptors bind amylin with high affinity but AMY_1(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, AMY_3(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 AMY_1(a) and AMY_3(a) receptors shows that there are some differences between species [5].

CGRP
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 CGRP_8-37 [54]. There are high affinity, non-peptide antagonists of CGRP receptors [3,49,58], the best characterised of which is BIBN4096BS [19]. CGRP_8-37 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.

AM_1-2
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 AM_22-52. 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.

CT
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.

AMY_1-3
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.

CGRP
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 CGRP_8-37. 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].

AM_1-2
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 CGRP_8-37. Linear agonists such as [Cys^2,7 acetamidomethyl]-CGRP showed some selectivity for these tissues [18,54]. Receptors which responded to CGRP but were weakly antagonised by CGRP_8-37 were known as CGRP₂ receptors. It now seems likely that this CGRP₂ receptor phenotype is due to expression of the AM₂ and AMY_1(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.

1. 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]

2. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature, 298 (5871): 240-4. [PMID:6283379]

3. Archbold JK, Flanagan JU, Watkins HA, Gingell JJ, Hay DL. (2011) Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development. Trends Pharmacol Sci, 32 (10): 591-600. [PMID:21722971]

4. Arulmani U, Schuijt MP, Heiligers JP, Willems EW, Villalón CM, Saxena PR. (2004) Effects of the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS on alpha-CGRP-induced regional haemodynamic changes in anaesthetised rats. Basic Clin Pharmacol Toxicol, 94 (6): 291-7. [PMID:15228501]

5. Bailey RJ, Walker CS, Ferner AH, Loomes KM, Prijic G, Halim A, Whiting L, Phillips AR, Hay DL. (2012) Pharmacological characterization of rat amylin receptors: implications for the identification of amylin receptor subtypes. Br J Pharmacol, 166 (1): 151-67. [PMID:22014233]

6. Bomberger JM, Parameswaran N, Hall CS, Aiyar N, Spielman WS. (2005) Novel function for receptor activity-modifying proteins (RAMPs) in post-endocytic receptor trafficking. J Biol Chem, 280 (10): 9297-307. [PMID:15613468]

7. 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]

8. Brain SD, Grant AD. (2004) Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev, 84 (3): 903-34. [PMID:15269340]

9. Brain SD, Poyner DR, Hill RG. (2002) CGRP receptors: a headache to study, but will antagonists prove therapeutic in migraine?. Trends Pharmacol Sci, 23 (2): 51-3. [PMID:11830255]

10. Caron KM, Smithies O. (2001) Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene. Proc Natl Acad Sci USA, 98 (2): 615-9. [PMID:11149956]

11. Chambers TJ, Magnus CJ. (1982) Calcitonin alters behaviour of isolated osteoclasts. J Pathol, 136 (1): 27-39. [PMID:7057295]

12. Chiba T, Yamaguchi A, Yamatani T, Nakamura A, Morishita T, Inui T, Fukase M, Noda T, Fujita T. (1989) Calcitonin gene-related peptide receptor antagonist human CGRP-(8-37). Am J Physiol, 256 (2 Pt 1): E331-5. [PMID:2537579]

13. 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]

14. Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB. (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA, 84 (23): 8628-32. [PMID:3317417]

15. Cornish J, Callon KE, Lin CQ, Xiao CL, Gamble GD, Cooper GJ, Reid IR. (1999) Comparison of the effects of calcitonin gene-related peptide and amylin on osteoblasts. J Bone Miner Res, 14 (8): 1302-9. [PMID:10457262]

16. Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA, Goldring SR, Gebre-Medhin S, Galson DL, Zajac JD, Karsenty G. (2004) Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol, 164 (4): 509-14. [PMID:14970190]

17. Davey RA, Turner A, McManus JF, Chiu WS, Tjahyono F, Moore AJ, Atkins GJ, Anderson PH, Ma C, Glatt V, Maclean HE, Vincent C, Bouxsein M, Morris HA, Findlay DM, Zajac JD. (2008) The Calcitonin Receptor Plays a Physiological Role to Protect Against Hypercalcemia in Mice. J Bone Miner Res, 8: 1182-1193. [PMID:18627265]

18. Dennis T, Fournier A, St Pierre S, Quirion R. (1989) Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity. J Pharmacol Exp Ther, 251 (2): 718-25. [PMID:2553933]

19. 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]

20. Felsenfeld AJ, Levine BS. (2015) Calcitonin, the forgotten hormone: does it deserve to be forgotten?. Clin Kidney J, 8 (2): 180-7. [PMID:25815174]

21. Fritz-Six KL, Dunworth WP, Li M, Caron KM. (2008) Adrenomedullin signaling is necessary for murine lymphatic vascular development. J Clin Invest, 118 (1): 40-50. [PMID:18097475]

22. Gebre-Medhin S, Mulder H, Pekny M, Westermark G, Törnell J, Westermark P, Sundler F, Ahrén B, Betsholtz C. (1998) Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin). Biochem Biophys Res Commun, 250 (2): 271-7. [PMID:9753619]

23. Gorn AH, Lin HY, Yamin M, Auron PE, Flannery MR, Tapp DR, Manning CA, Lodish HF, Krane SM, Goldring SR. (1992) Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line. J Clin Invest, 90 (5): 1726-35. [PMID:1331173]

24. Hay DL. (2007) What makes a CGRP2 receptor?. Clin Exp Pharmacol Physiol, 34 (10): 963-71. [PMID:17714080]

25. Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. (2015) Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacol Rev, 67 (3): 564-600. [PMID:26071095]

26. 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]

27. 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]

28. 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]

29. 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]

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

31. 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]

32. Hay DL, Poyner DR, Sexton PM. (2006) GPCR modulation by RAMPs. Pharmacol Ther, 109 (1-2): 173-97. [PMID:16111761]

33. Hinson JP, Kapas S, Smith DM. (2000) Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev, 21 (2): 138-67. [PMID:10782362]

34. Hoare SR. (2005) Mechanisms of peptide and nonpeptide ligand binding to Class B G-protein-coupled receptors. Drug Discov Today, 10 (6): 417-27. [PMID:15808821]

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

36. Ichikawa-Shindo Y, Sakurai T, Kamiyoshi A, Kawate H, Iinuma N, Yoshizawa T, Koyama T, Fukuchi J, Iimuro S, Moriyama N et al.. (2008) The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity. J Clin Invest, 118 (1): 29-39. [PMID:18097473]

37. Kahn ML. (2008) Blood is thicker than lymph. J Clin Invest, 118 (1): 23-6. [PMID:18097477]

38. Kapoor K, Arulmani U, Heiligers JP, Garrelds IM, Willems EW, Doods H, Villalón CM, Saxena PR. (2003) Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Br J Pharmacol, 140 (2): 329-38. [PMID:12970078]

39. Kapoor K, Arulmani U, Heiligers JP, Willems EW, Doods H, Villalón CM, Saxena PR. (2003) Effects of BIBN4096BS on cardiac output distribution and on CGRP-induced carotid haemodynamic responses in the pig. Eur J Pharmacol, 475 (1-3): 69-77. [PMID:12954361]

40. Katafuchi T, Hamano K, Kikumoto K, Minamino N. (2003) Identification of second and third calcitonin receptor-stimulating peptides in porcine brain. Biochem Biophys Res Commun, 308 (3): 445-51. [PMID:12914769]

41. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun, 192 (2): 553-60. [PMID:8387282]

42. Kusano S, Kukimoto-Niino M, Akasaka R, Toyama M, Terada T, Shirouzu M, Shindo T, Yokoyama S. (2008) Crystal structure of the human receptor activity-modifying protein 1 extracellular domain. Protein Sci, 17 (11): 1907-14. [PMID:18725456]

43. 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]

44. Lin HY, Harris TL, Flannery MS, Aruffo A, Kaji EH, Gorn A, Kolakowski Jr LF, Lodish HF, Goldring SR. (1991) Expression cloning of an adenylate cyclase-coupled calcitonin receptor. Science, 254 (5034): 1022-4. [PMID:1658940]

45. 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]

46. Masi L, Becherini L, Gennari L, Colli E, Mansani R, Falchetti A, Cepollaro C, Gonnelli S, Tanini A, Brandi ML. (1998) Allelic variants of human calcitonin receptor: distribution and association with bone mass in postmenopausal Italian women. Biochem Biophys Res Commun, 245 (2): 622-6. [PMID:9571205]

47. 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]

48. Mitsikostas DD, Rapoport AM. (2015) New players in the preventive treatment of migraine. BMC Med, 13: 279. [PMID:26555040]

49. Moore EL, Salvatore CA. (2012) Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine. Br J Pharmacol, 166 (1): 66-78. [PMID:21871019]

50. Mulderry PK, Ghatei MA, Spokes RA, Jones PM, Pierson AM, Hamid QA, Kanse S, Amara SG, Burrin JM, Legon S et al.. (1988) Differential expression of alpha-CGRP and beta-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience, 25 (1): 195-205. [PMID:2839796]

51. Nakamura M, Zhang ZQ, Shan L, Hisa T, Sasaki M, Tsukino R, Yokoi T, Kaname A, Kakudo K. (1997) Allelic variants of human calcitonin receptor in the Japanese population. Hum Genet, 99 (1): 38-41. [PMID:9003491]

52. Petersen KA, Birk S, Lassen LH, Kruuse C, Jonassen O, Lesko L, Olesen J. (2005) The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers. Cephalalgia, 25 (2): 139-47. [PMID:15658951]

53. Piao FL, Cao C, Han JH, Kim SZ, Cho KW, Kim SH. (2004) Amylin-induced suppression of ANP secretion through receptors for CGRP1 and salmon calcitonin. Regul Pept, 117: 159-166. [PMID:14749035]

54. 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]

55. Purdue BW, Tilakaratne N, Sexton PM. (2002) Molecular pharmacology of the calcitonin receptor. Recept Channels, 8 (3-4): 243-55. [PMID:12529940]

56. Roh J, Chang CL, Bhalla A, Klein C, Hsu SY. (2004) Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem, 279 (8): 7264-74. [PMID:14615490]

57. 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]

58. 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]

59. Schütz B, Mauer D, Salmon AM, Changeux JP, Zimmer A. (2004) Analysis of the cellular expression pattern of beta-CGRP in alpha-CGRP-deficient mice. J Comp Neurol, 476 (1): 32-43. [PMID:15236465]

60. Shindo T, Kurihara Y, Nishimatsu H, Moriyama N, Kakoki M, Wang Y, Imai Y, Ebihara A, Kuwaki T, Ju KH et al.. (2001) Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene. Circulation, 104 (16): 1964-71. [PMID:11602502]

61. Smillie SJ, Brain SD. (2011) Calcitonin gene-related peptide (CGRP) and its role in hypertension. Neuropeptides, 45 (2): 93-104. [PMID:21269690]

62. Taboulet J, Frenkian M, Frendo JL, Feingold N, Jullienne A, de Vernejoul MC. (1998) Calcitonin receptor polymorphism is associated with a decreased fracture risk in post-menopausal women. Hum Mol Genet, 7 (13): 2129-33. [PMID:9817931]

63. Takei Y, Inoue K, Ogoshi M, Kawahara T, Bannai H, Miyano S. (2004) Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator. FEBS Lett, 556 (1-3): 53-8. [PMID:14706825]

64. 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]

65. Uezono Y, Nakamura E, Ueda Y, Shibuya I, Ueta Y, Yokoo H, Yanagita T, Toyohira Y, Kobayashi H, Yanagihara N et al.. (2001) Production of cAMP by adrenomedullin in human oligodendroglial cell line KG1C: comparison with calcitonin gene-related peptide and amylin. Brain Res Mol Brain Res, 97 (1): 59-69. [PMID:11744163]

66. Villa I, Melzi R, Pagani F, Ravasi F, Rubinacci A, Guidobono F. (2000) Effects of calcitonin gene-related peptide and amylin on human osteoblast-like cells proliferation. Eur J Pharmacol, 409: 273-278. [PMID:11108821]

67. 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]

68. Walker CS, Hay DL. (2013) CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?. Br J Pharmacol, 170 (7): 1293-307. [PMID:23425327]

69. Wolfe 3rd LA, Fling ME, Xue Z, Armour S, Kerner SA, Way J, Rimele T, Cox RF. (2003) In vitro characterization of a human calcitonin receptor gene polymorphism. Mutat Res, 522 (1-2): 93-105. [PMID:12517415]

70. Young AA, Gedulin B, Gaeta LS, Prickett KS, Beaumont K, Larson E, Rink TJ. (1994) Selective amylin antagonist suppresses rise in plasma lactate after intravenous glucose in the rat. Evidence for a metabolic role of endogenous amylin. FEBS Lett, 343 (3): 237-41. [PMID:8174707]