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CGRP Receptor Biology: Is There More Than One Receptor?

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Calcitonin Gene-Related Peptide (CGRP) Mechanisms

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 255))

Abstract

Calcitonin gene-related peptide (CGRP) has many reported pharmacological actions. Can a single receptor explain all of these? This chapter outlines the molecular nature of reported CGRP binding proteins and their pharmacology. Consideration of whether CGRP has only one or has more receptors is important because of the key role that this peptide plays in migraine. It is widely thought that the calcitonin receptor-like receptor together with receptor activity-modifying protein 1 (RAMP1) is the only relevant receptor for CGRP. However, some closely related receptors also have high affinity for CGRP and it is still plausible that these play a role in CGRP biology, and in migraine. The calcitonin receptor/RAMP1 complex, which is currently called the AMY1 receptor, seems to be the most likely candidate but more investigation is needed to determine its role.

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References

  • Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, Li Y (1996) A cDNA encoding the calcitonin gene-related peptide type 1 receptor. J Biol Chem 271(19):11325–11329

    Article  CAS  Google Scholar 

  • Aiyar N, Disa J, Ao Z, Xu D, Surya A, Pillarisetti K, Parameswaran N, Gupta SK, Douglas SA, Nambi P (2002) Molecular cloning and pharmacological characterization of bovine calcitonin receptor-like receptor from bovine aortic endothelial cells. Biochem Pharmacol 63(11):1949–1959

    Article  CAS  Google Scholar 

  • Bailey RJ, Walker CS, Ferner AH, Loomes KM, Prijic G, Halim A, Whiting L, Phillips ARJ, Hay DL (2012) Pharmacological characterisation of rat amylin receptors: implications for the identification of amylin receptor subtypes. Br J Pharmacol 166(1):151–167. https://doi.org/10.1111/j.1476-5381.2011.01717.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Booe JM, Walker CS, Barwell J, Kuteyi G, Simms J, Jamaluddin MA, Warner ML, Bill RM, Harris PW, Brimble MA, Poyner DR, Hay DL, Pioszak AA (2015) Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor. Mol Cell 58(6):1040–1052. https://doi.org/10.1016/j.molcel.2015.04.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chakravarty P, Suthar TP, Coppock HA, Nicholl CG, Bloom SR, Legon S, Smith DM (2000) CGRP and adrenomedullin binding correlates with transcript levels for calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) in rat tissues. Br J Pharmacol 130(1):189–195

    Article  CAS  Google Scholar 

  • Christopoulos G, Perry K, Morfis M, Tilakaratne N, Gao Y, Fraser NJ, Main MJ, Foord SM, Sexton PM (1999) Multiple amylin receptors arise from receptor-activity-modifying-proteins interaction with the calcitonin receptor gene product. Mol Pharmacol 56:235–242

    Article  CAS  Google Scholar 

  • Dennis T, Fournier A, Cadieux A, Pomerleau F, Jolicoeur FB, St. Pierre S, Quirion R (1990) hCGRP8-37, a calcitonin gene-related peptide antagonist revealing calcitonin gene-related peptide receptor heterogeneity in brain and periphery. J Pharmacol Exp Ther 254(1):123–128

    CAS  PubMed  Google Scholar 

  • Elshourbagy NA, Adamou JE, Swift AM, Disa J, Mao J, Ganguly S, Bergsma DJ, Aiyar N (1998) Molecular cloning and characterization of the porcine calcitonin gene-related peptide receptor. Endocrinology 139(4):1678–1683

    Article  CAS  Google Scholar 

  • Fluhmann B, Muff R, Hunziker W, Fischer JA, Born W (1995) A human orphan calcitonin receptor-like structure. Biochem Biophys Res Commun 206(1):341–347

    Article  CAS  Google Scholar 

  • Foord SM, Wise A, Brown J, Main MJ, Fraser NJ (1999) The N-terminus of RAMPs is a critical determinant of the glycosylation state and ligand binding of calcitonin receptor-like receptor. Biochem Soc Trans 27(4):535–539

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Furness SGB, Wootten D, Christopoulos A, Sexton PM (2012) Consequences of splice variation on secretin family G protein-coupled receptor function. Br J Pharmacol 166(1):98–109. https://doi.org/10.1111/j.1476-5381.2011.01571.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halim A, Hay DL (2012) The role of glutamic acid 73 in adrenomedullin interactions with rodent AM2 receptors. Peptides 36(1):137–141. https://doi.org/10.1016/j.peptides.2012.04.011

    Article  CAS  PubMed  Google Scholar 

  • Han ZQ, Coppock HA, Smith DM, Van Noorden S, Makgoba MW, Nicholl CG, Legon S (1997) The interaction of CGRP and adrenomedullin with a receptor expressed in the rat pulmonary vascular endothelium. J Mol Endocrinol 18(3):267–272

    Article  CAS  Google Scholar 

  • Hanze J, Dittrich K, Dotsch J, Rascher W (1997) Molecular cloning of a novel human receptor gene with homology to the rat adrenomedullin receptor and high expression in heart and immune system. Biochem Biophys Res Commun 240(1):183–188

    Article  CAS  Google Scholar 

  • Hay DL, Walker CS (2017) CGRP and its receptors. Headache 57(4):625–636. https://doi.org/10.1111/head.13064

    Article  PubMed  Google Scholar 

  • Hay DL, Howitt SG, Conner AC, Doods H, Schindler M, Poyner DR (2002) A comparison of the actions of BIBN4096BS and CGRP8-37 on CGRP and adrenomedullin receptors expressed on SK-N-MC, L6, Col 29 and Rat 2 cells. Br J Pharmacol 137(1):80

    Article  CAS  Google Scholar 

  • 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):477–486

    Article  CAS  Google Scholar 

  • 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):1655–1665. https://doi.org/10.1124/mol.104.008615

    Article  CAS  PubMed  Google Scholar 

  • 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-d ibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazoliny l) (BIBN4096BS) affinity for calcitonin gene-related peptide and amylin receptors – the role of receptor activity modifying protein 1. Mol Pharmacol 70(6):1984–1991. https://doi.org/10.1124/mol.106.027953

    Article  CAS  PubMed  Google Scholar 

  • Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD (2015) Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev 67(3):564–600. https://doi.org/10.1124/pr.115.010629

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1111/bph.14075

    Article  CAS  PubMed  Google Scholar 

  • Husmann K, Sexton PM, Fischer JA, Born W (2000) Mouse receptor-activity-modifying proteins 1, -2 and -3: amino acid sequence, expression and function. Mol Cell Endocrinol 162(1–2):35–43

    Article  CAS  Google Scholar 

  • Juaneda C, Dumont Y, Quirion R (2000) The molecular pharmacology of CGRP and related peptide receptor subtypes. Trends Pharmacol Sci 21:432–438

    Article  CAS  Google Scholar 

  • Kapas S, Clark AJ (1995) Identification of an orphan receptor gene as a type 1 calcitonin gene-related peptide receptor. Biochem Biophys Res Commun 217(3):832–838

    Article  CAS  Google Scholar 

  • Kapas S, Catt KJ, Clark AJ (1995) Cloning and expression of cDNA encoding a rat adrenomedullin receptor. J Biol Chem 270(43):25344–25347

    Article  CAS  Google Scholar 

  • Kennedy SP, Sun D, Oleynek JJ, Hoth CF, Kong J, Hill RJ (1998) Expression of the rat adrenomedullin receptor or a putative human adrenomedullin receptor does not correlate with adrenomedullin binding or functional response. Biochem Biophys Res Commun 244:832–837

    Article  CAS  Google Scholar 

  • Klein KR, Karpinich NO, Espenschied ST, Willcockson HH, Dunworth WP, Hoopes SL, Kushner EJ, Bautch VL, Caron KM (2014) Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development. Dev Cell 30(5):528–540. https://doi.org/10.1016/j.devcel.2014.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kusano S, Kukimoto-Niino M, Hino N, Ohsawa N, Okuda K-I, Sakamoto K, Shirouzu M, Shindo T, Yokoyama S (2012) Structural basis for extracellular interactions between calcitonin receptor-like receptor and receptor activity-modifying protein 2 for adrenomedullin-specific binding. Protein Sci 21(2):199–210. https://doi.org/10.1002/pro.2003

    Article  CAS  PubMed  Google Scholar 

  • Kuwasako K, Cao Y-N, 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):207–213

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Luebke AE, Dahl GP, Roos BA, Dickerson IM (1996) Identification of a protein that confers calcitonin gene-related peptide responsiveness to oocytes by using a cystic fibrosis transmembrane conductance regulator assay. Proc Natl Acad Sci U S A 93(8):3455–3460

    Article  CAS  Google Scholar 

  • 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):333–339

    Article  CAS  Google Scholar 

  • Miyauchi K, Tadotsu N, Hayashi T, Ono Y, Tokoyoda K, Tsujikawa K, Yamamoto H (2002) Molecular cloning and characterization of mouse calcitonin gene-related peptide receptor. Neuropeptides 36(1):22–33

    Article  CAS  Google Scholar 

  • 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. https://doi.org/10.1111/j.1476-5381.2011.01633.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagae T, Mukoyama M, Sugawara A, Mori K, Yahata K, Kasahara M, Suganami T, Makino H, Fujinaga Y, Yoshioka T, Tanaka K, Nakao K (2000) Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy. Biochem Biophys Res Commun 270:89–93

    Article  CAS  Google Scholar 

  • Njuki F, Nicholl CG, Howard A, Mak JCW, Barnes PJ, Girgis SI, Legon S (1993) A new calcitonin-receptor-like sequence in rat pulmonary blood vessels. Clin Sci 85:385–388

    Article  CAS  Google Scholar 

  • Oliver KR, Kane SA, Salvatore CA, Mallee JJ, Kinsey AM, Koblan KS, Keyvan-Fouladi N, Heavens RP, Wainwright A, Jacobson M, Dickerson IM, Hill RG (2001) Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat. Eur J Neurosci 14(4):618–628. https://doi.org/10.1046/j.0953-816x.2001.01688.x

    Article  CAS  PubMed  Google Scholar 

  • Poyner D (1995) Pharmacology of receptors for calcitonin gene-related peptide and amylin. Trends Pharmacol Sci 16(12):424–428

    Article  CAS  Google Scholar 

  • 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):233–246

    Article  CAS  Google Scholar 

  • 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):644–657. https://doi.org/10.1111/j.1476-5381.2012.02197.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM (2010) Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure 18(9):1083–1093. https://doi.org/10.1016/j.str.2010.05.014

    Article  CAS  PubMed  Google Scholar 

  • Salvatore CA, Moore EL, Calamari A, Cook JJ, Michener MS, O’Malley S, Miller PJ, Sur C, Williams DL Jr, Zeng Z, Danziger A, Lynch JJ, Regan CP, Fay JF, Tang YS, Li CC, Pudvah NT, White RB, Bell IM, Gallicchio SN, Graham SL, Selnick HG, Vacca JP, Kane SA (2010) Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist. J Pharmacol Exp Ther 333(1):152–160. https://doi.org/10.1124/jpet.109.163816

    Article  CAS  PubMed  Google Scholar 

  • Sekiguchi T, Kuwasako K, Ogasawara M, Takahashi H, Matsubara S, Osugi T, Muramatsu I, Sasayama Y, Suzuki N, Satake H (2016) Evidence for conservation of the calcitonin superfamily and activity-regulating mechanisms in the basal chordate Branchiostoma floridae: insights into the molecular and functional evolution in chordates. J Biol Chem 291(5):2345–2356. https://doi.org/10.1074/jbc.M115.664003

    Article  CAS  PubMed  Google Scholar 

  • Shi L, Lehto SG, Zhu DXD, Sun H, Zhang J, Smith BP, Immke DC, Wild KD, Xu C (2016) Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J Pharmacol Exp Ther 356(1):223–231. https://doi.org/10.1124/jpet.115.227793

    Article  CAS  PubMed  Google Scholar 

  • Suzuki N, Suzuki T, Kurokawa T (2000) Cloning of a calcitonin gene-related peptide receptor and a novel calcitonin receptor-like receptor from the gill of the flounder, Paralichthys olivaceus. Gene 244:81–88

    Article  CAS  Google Scholar 

  • 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 294:61–72

    CAS  PubMed  Google Scholar 

  • Walker CS, Conner AC, Poyner DR, Hay DL (2010) Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol Sci 31(10):476–483. https://doi.org/10.1016/j.tips.2010.06.006

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1002/acn3.197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker CS, Raddant AC, Woolley MJ, Russo AF, Hay DL (2017) CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. Cephalalgia 38(3):437–451. https://doi.org/10.1177/0333102417691762

    Article  PubMed  PubMed Central  Google Scholar 

  • Watkins HA, Rathbone DL, Barwell J, Hay DL, Poyner DR (2013) Structure-activity relationships for alpha-calcitonin gene-related peptide. Br J Pharmacol 170(7):1308–1322. https://doi.org/10.1111/bph.12072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, Mobarec JC, Woodlock DA, Reynolds CA, Poyner DR, Watkins HA, Ladds G (2016) Receptor activity-modifying protein-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors. J Biol Chem 291(42):21925–21944. https://doi.org/10.1074/jbc.M116.751362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. School of Biological Sciences, The University of Auckland, Auckland, New Zealand

    Debbie L. Hay

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  1. Debbie L. Hay
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Correspondence to Debbie L. Hay .

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Editors and Affiliations

  1. School of Cardiovascular Medicine & Sciences, King’s College London, London, UK

    Susan D. Brain

  2. Department of Health Sciences, University of Florence, Florence, Italy

    Pierangelo Geppetti

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Hay, D.L. (2018). CGRP Receptor Biology: Is There More Than One Receptor?. In: Brain, S., Geppetti, P. (eds) Calcitonin Gene-Related Peptide (CGRP) Mechanisms. Handbook of Experimental Pharmacology, vol 255. Springer, Cham. https://doi.org/10.1007/164_2018_131

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