Abstract
Calcitonin gene-related peptide (CGRP) is a promiscuous peptide, similar to many other members of the calcitonin family of peptides. The potential of CGRP to act on many different receptors with differing affinities and efficacies makes deciphering the signalling from the CGRP receptor a challenging task for researchers.
Although it is not a typical G protein-coupled receptor (GPCR), in that it is composed not just of a GPCR, the CGRP receptor activates many of the same signalling pathways common for other GPCRs. This includes the family of G proteins and a variety of protein kinases and transcription factors. It is now also clear that in addition to the initiation of cell-surface signalling, GPCRs, including the CGRP receptor, also activate distinct signalling pathways as the receptor is trafficking along the endocytic conduit.
Given CGRP’s characteristic of activating multiple GPCRs, we will first consider the complex of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) as the CGRP receptor. We will discuss the discovery of the CGRP receptor components, the molecular mechanisms controlling its internalization and post-endocytic trafficking (recycling and degradation) and the diverse signalling cascades that are elicited by this receptor in model cell lines. We will then discuss CGRP-mediated signalling pathways in primary cells pertinent to migraine including neurons, glial cells and vascular smooth muscle cells.
Investigation of all the CGRP- and CGRP receptor-mediated signalling cascades is vital if we are to fully understand CGRP’s role in migraine and will no doubt unearth new targets for the treatment of migraine and other CGRP-driven diseases.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
Abbreviations
- ATP:
-
Adenosine triphosphate
- cAMP:
-
Cyclic adenosine monophosphate
- CGRP:
-
Calcitonin gene-related peptide
- CLR:
-
Calcitonin receptor-like receptor
- ECE1:
-
Endothelin-converting enzyme 1
- ERK:
-
Extracellular-regulated protein kinase
- ETA :
-
Endothelin A receptor
- GPCR:
-
G protein-coupled receptor
- IL:
-
Interleukin
- JNK:
-
c-Jun N-terminal kinase
- PKA:
-
Protein kinase A
- PKC:
-
Protein kinase C
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
- RAMP:
-
Receptor activity-modifying protein
- RCP:
-
Receptor component protein
References
Abushik PA et al (2016) Pro-nociceptive migraine mediator CGRP provides neuroprotection of sensory, cortical and cerebellar neurons via multi-kinase signaling. Cephalalgia. https://doi.org/10.1177/0333102416681588
Aiyar N, Disa J, Dang K, Pronin AN, Benovic JL, Nambi P (2000) Involvement of G protein-coupled receptor kinase-6 in desensitization of CGRP receptors. Eur J Pharmacol 403:1–7
Aiyar N, Disa J, Stadel JM, Lysko PG (1999) Calcitonin gene-related peptide receptor independently stimulates 3′,5′-cyclic adenosine monophosphate and Ca2+ signaling pathways. Mol Cell Biochem 197:179–185
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 298:240–244
Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S (1990) Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348:730–732. https://doi.org/10.1038/348730a0
Bache KG, Raiborg C, Mehlum A, Stenmark H (2003) STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes. J Biol Chem 278:12513–12521. https://doi.org/10.1074/jbc.M210843200
Banerjee S, Evanson J, Harris E, Lowe SL, Thomasson KA, Porter JE (2006) Identification of specific calcitonin-like receptor residues important for calcitonin gene-related peptide high affinity binding. BMC Pharmacol 6:9. https://doi.org/10.1186/1471-2210-6-9
Bautista DM et al (2005) Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci U S A 102:12248–12252. https://doi.org/10.1073/pnas.0505356102
Borkum JM (2018) The migraine attack as a homeostatic, neuroprotective response to brain oxidative stress: preliminary evidence for a theory. Headache 58:118–135. https://doi.org/10.1111/head.13214
Budenholzer L, Cheng CL, Li Y, Hochstrasser M (2017) Proteasome structure and assembly. J Mol Biol 429:3500–3524. https://doi.org/10.1016/j.jmb.2017.05.027
Buldyrev I, Tanner NM, Hsieh HY, Dodd EG, Nguyen LT, Balkowiec A (2006) Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons. J Neurochem 99:1338–1350. https://doi.org/10.1111/j.1471-4159.2006.04161.x
Cady RJ, Glenn JR, Smith KM, Durham PL (2011) Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain 7:94. https://doi.org/10.1186/1744-8069-7-94
Ceruti S et al (2011) Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 knock-in mice: implications for basic mechanisms of migraine pain. J Neurosci 31:3638–3649. https://doi.org/10.1523/JNEUROSCI.6440-10.2011
Cottrell GS, Padilla B, Pikios S, Roosterman D, Steinhoff M, Grady EF, Bunnett NW (2007) Post-endocytic sorting of calcitonin receptor-like receptor and receptor activity-modifying protein 1. J Biol Chem 282:12260–12271. https://doi.org/10.1074/jbc.M606338200
Cottrell GS et al (2009) Endosomal endothelin-converting enzyme-1: a regulator of beta-arrestin-dependent ERK signaling. J Biol Chem 284:22411–22425. https://doi.org/10.1074/jbc.M109.026674
Cottrell GS et al (2005) Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat. J Comp Neurol 490:239–255. https://doi.org/10.1002/cne.20669
De Mey JG, Compeer MG, Lemkens P, Meens MJ (2011) ETA-receptor antagonists or allosteric modulators? Trends Pharmacol Sci 32:345–351. https://doi.org/10.1016/j.tips.2011.02.018
De Mey JG, Compeer MG, Meens MJ (2009) Endothelin-1, an endogenous irreversible agonist in search of an allosteric inhibitor. Mol Cell Pharmacol 1:246–257
DeFea KA, Vaughn ZD, O’Bryan EM, Nishijima D, Dery O, Bunnett NW (2000) The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta-arrestin-dependent scaffolding complex. Proc Natl Acad Sci U S A 97:11086–11091. https://doi.org/10.1073/pnas.190276697
Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117:3720–3732. https://doi.org/10.1182/blood-2010-07-273417
Doi Y et al (2001) Synthesis of calcitonin gene-related peptide (CGRP) by rat arterial endothelial cells. Histol Histopathol 16:1073–1079
Edvinsson L, Alm R, Shaw D, Rutledge RZ, Koblan KS, Longmore J, Kane SA (2002) Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells. Eur J Pharmacol 434:49–53
Edvinsson L, Fredholm BB, Hamel E, Jansen I, Verrecchia C (1985) Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation or release of an endothelium-derived relaxing factor in the cat. Neurosci Lett 58:213–217
Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L (2010) Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 169:683–696. https://doi.org/10.1016/j.neuroscience.2010.05.016
Egea SC, Dickerson IM (2012) Direct interactions between calcitonin-like receptor (CLR) and CGRP-receptor component protein (RCP) regulate CGRP receptor signaling. Endocrinology 153:1850–1860. https://doi.org/10.1210/en.2011-1459
Eichel K, von Zastrow M (2018) Subcellular organization of GPCR signaling. Trends Pharmacol Sci 39:200–208. https://doi.org/10.1016/j.tips.2017.11.009
Evans BN, Rosenblatt MI, Mnayer LO, Oliver KR, Dickerson IM (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 275:31438–31443. https://doi.org/10.1074/jbc.M005604200
Fabbretti E (2013) ATP P2X3 receptors and neuronal sensitization. Front Cell Neurosci 7:236. https://doi.org/10.3389/fncel.2013.00236
Fabbretti E, D’Arco M, Fabbro A, Simonetti M, Nistri A, Giniatullin R (2006) Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J Neurosci 26:6163–6171. https://doi.org/10.1523/JNEUROSCI.0647-06.2006
Fahnoe DC, Knapp J, Johnson GD, Ahn K (2000) Inhibitor potencies and substrate preference for endothelin-converting enzyme-1 are dramatically affected by pH. J Cardiovasc Pharmacol 36:S22–S25
Feinstein TN et al (2013) Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. J Biol Chem 288:27849–27860. https://doi.org/10.1074/jbc.M112.445098
Ferrandon S et al (2009) Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol 5:734–742. https://doi.org/10.1038/nchembio.206
Fischer MJ, Koulchitsky S, Messlinger K (2005) The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus. J Neurosci 25:5877–5883. https://doi.org/10.1523/JNEUROSCI.0869-05.2005
Fraser NJ, Wise A, Brown J, McLatchie LM, Main MJ, Foord SM (1999) The amino terminus of receptor activity modifying proteins is a critical determinant of glycosylation state and ligand binding of calcitonin receptor-like receptor. Mol Pharmacol 55:1054–1059
Fujimori A, Saito A, Kimura S, Goto K (1990) Release of calcitonin gene-related peptide (CGRP) from capsaicin-sensitive vasodilator nerves in the rat mesenteric artery. Neurosci Lett 112:173–178
Gao YJ, Ji RR (2009) c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? Open Pain J 2:11–17. https://doi.org/10.2174/1876386300902010011
Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE (1995) ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J 14:951–962
Grace GC, Dusting GJ, Kemp BE, Martin TJ (1987) Endothelium and the vasodilator action of rat calcitonin gene-related peptide (CGRP). Br J Pharmacol 91:729–733
Guillemare E, Lazdunski M, Honore E (1994) CGRP-induced activation of KATP channels in follicular Xenopus oocytes. Pflugers Arch 428:604–609
Gurevich VV, Gurevich EV (2015) Analyzing the roles of multi-functional proteins in cells: the case of arrestins and GRKs. Crit Rev Biochem Mol Biol 50:440–452. https://doi.org/10.3109/10409238.2015.1067185
Haegerstrand A, Dalsgaard CJ, Jonzon B, Larsson O, Nilsson J (1990) Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc Natl Acad Sci U S A 87:3299–3303
Hagner S et al (2001) Immunohistochemical detection of calcitonin gene-related peptide receptor (CGRPR)-1 in the endothelium of human coronary artery and bronchial blood vessels. Neuropeptides 35:58–64. https://doi.org/10.1054/npep.2000.0844
Hanko J, Hardebo JE, Kahrstrom J, Owman C, Sundler F (1985) Calcitonin gene-related peptide is present in mammalian cerebrovascular nerve fibres and dilates pial and peripheral arteries. Neurosci Lett 57:91–95
Hanyaloglu AC, McCullagh E, von Zastrow M (2005) Essential role of Hrs in a recycling mechanism mediating functional resensitization of cell signaling. EMBO J 24:2265–2283. https://doi.org/10.1038/sj.emboj.7600688
Hasdemir B, Bunnett NW, Cottrell GS (2007) Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor. J Biol Chem 282:29646–29657. https://doi.org/10.1074/jbc.M702974200
Hay DL, Pioszak AA (2016) Receptor activity-modifying proteins (RAMPs): new insights and roles. Annu Rev Pharmacol Toxicol 56:469–487. https://doi.org/10.1146/annurev-pharmtox-010715-103120
Hershko A, Ciechanover A, Heller H, Haas AL, Rose IA (1980) Proposed role of ATP in protein breakdown: conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proc Natl Acad Sci U S A 77:1783–1786
Herskovits JS, Burgess CC, Obar RA, Vallee RB (1993) Effects of mutant rat dynamin on endocytosis. J Cell Biol 122:565–578
Herzog M, Scherer EQ, Albrecht B, Rorabaugh B, Scofield MA, Wangemann P (2002) CGRP receptors in the gerbil spiral modiolar artery mediate a sustained vasodilation via a transient cAMP-mediated Ca2+-decrease. J Membr Biol 189:225–236. https://doi.org/10.1007/s00232-002-1017-5
Hesse G (2016) Evidence and evidence gaps in tinnitus therapy. GMS Curr Top Otorhinolaryngol Head Neck Surg 15:Doc04. https://doi.org/10.3205/cto000131
Hilairet S, Belanger C, Bertrand J, Laperriere A, Foord SM, Bouvier M (2001) Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activity-modifying protein 1 (RAMP1), and beta-arrestin. J Biol Chem 276:42182–42190. https://doi.org/10.1074/jbc.M107323200
Hill K, Schaefer M (2009) Ultraviolet light and photosensitising agents activate TRPA1 via generation of oxidative stress. Cell Calcium 45:155–164. https://doi.org/10.1016/j.ceca.2008.08.001
Hislop JN, Marley A, Von Zastrow M (2004) Role of mammalian vacuolar protein-sorting proteins in endocytic trafficking of a non-ubiquitinated G protein-coupled receptor to lysosomes. J Biol Chem 279:22522–22531. https://doi.org/10.1074/jbc.M311062200
Ho AP et al (2010) Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia 30:1443–1457. https://doi.org/10.1177/0333102410370878
Hodge C, Liao J, Stofega M, Guan K, Carter-Su C, Schwartz J (1998) Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. J Biol Chem 273:31327–31336
Hori S, Komatsu Y, Shigemoto R, Mizuno N, Nakanishi S (1992) Distinct tissue distribution and cellular localization of two messenger ribonucleic acids encoding different subtypes of rat endothelin receptors. Endocrinology 130:1885–1895. https://doi.org/10.1210/endo.130.4.1312429
Hulsmann M, Nickel P, Kassack M, Schmalzing G, Lambrecht G, Markwardt F (2003) NF449, a novel picomolar potency antagonist at human P2X1 receptors. Eur J Pharmacol 470:1–7
Hunt SP, Pini A, Evan G (1987) Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 328:632–634. https://doi.org/10.1038/328632a0
Irannejad R et al (2013) Conformational biosensors reveal GPCR signalling from endosomes. Nature 495:534–538. https://doi.org/10.1038/nature12000
Irannejad R, von Zastrow M (2014) GPCR signaling along the endocytic pathway. Curr Opin Cell Biol 27:109–116. https://doi.org/10.1016/j.ceb.2013.10.003
Jacob C, Cottrell GS, Gehringer D, Schmidlin F, Grady EF, Bunnett NW (2005) c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem 280:16076–16087. https://doi.org/10.1074/jbc.M500109200
Jean-Charles PY, Kaur S, Shenoy SK (2017) G protein-coupled receptor signaling through beta-arrestin-dependent mechanisms. J Cardiovasc Pharmacol 70:142–158. https://doi.org/10.1097/FJC.0000000000000482
Jensen DD et al (2017) Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Sci Transl Med 9. https://doi.org/10.1126/scitranslmed.aal3447
Klein KR, Matson BC, Caron KM (2016) The expanding repertoire of receptor activity modifying protein (RAMP) function. Crit Rev Biochem Mol Biol 51:65–71. https://doi.org/10.3109/10409238.2015.1128875
Klein SL, Strausberg RL, Wagner L, Pontius J, Clifton SW, Richardson P (2002) Genetic and genomic tools for Xenopus research: the NIH Xenopus initiative. Dev Dyn 225:384–391. https://doi.org/10.1002/dvdy.10174
Kline LW, Kaneko T, Chiu KW, Harvey S, Pang PK (1988) Calcitonin gene-related peptide in the bullfrog, Rana catesbeiana: localization and vascular actions. Gen Comp Endocrinol 72:123–129
Kobayashi H et al (1987) Calcitonin gene related peptide stimulates adenylate cyclase activity in rat striated muscle. Experientia 43:314–316
Kobayashi K, Fukuoka T, Obata K, Yamanaka H, Dai Y, Tokunaga A, Noguchi K (2005) Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol 493:596–606. https://doi.org/10.1002/cne.20794
Komada M, Masaki R, Yamamoto A, Kitamura N (1997) Hrs, a tyrosine kinase substrate with a conserved double zinc finger domain, is localized to the cytoplasmic surface of early endosomes. J Biol Chem 272:20538–20544
Kristiansen KA, Edvinsson L (2010) Neurogenic inflammation: a study of rat trigeminal ganglion. J Headache Pain 11:485–495. https://doi.org/10.1007/s10194-010-0260-x
Kuwasako K, Kitamura K, Nagoshi Y, Cao YN, Eto T (2003) Identification of the human receptor activity-modifying protein 1 domains responsible for agonist binding specificity. J Biol Chem 278:22623–22630. https://doi.org/10.1074/jbc.M302571200
Kuwasako K et al (2000) Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling. J Biol Chem 275:29602–29609. https://doi.org/10.1074/jbc.M004534200
Laufer R, Changeux JP (1987) Calcitonin gene-related peptide elevates cyclic AMP levels in chick skeletal muscle: possible neurotrophic role for a coexisting neuronal messenger. EMBO J 6:901–906
Lecca D, Ceruti S, Fumagalli M, Abbracchio MP (2012) Purinergic trophic signalling in glial cells: functional effects and modulation of cell proliferation, differentiation, and death. Purinergic Signal 8:539–557. https://doi.org/10.1007/s11302-012-9310-y
Lehmann DM, Seneviratne AM, Smrcka AV (2008) Small molecule disruption of G protein beta gamma subunit signaling inhibits neutrophil chemotaxis and inflammation. Mol Pharmacol 73:410–418. https://doi.org/10.1124/mol.107.041780
Lei S, Mulvany MJ, Nyborg NC (1994) Characterization of the CGRP receptor and mechanisms of action in rat mesenteric small arteries. Pharmacol Toxicol 74:130–135
Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, Messlinger K (2008) Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol 507:1277–1299. https://doi.org/10.1002/cne.21607
Levy D, Burstein R, Strassman AM (2005) Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 58:698–705. https://doi.org/10.1002/ana.20619
Li J, Vause CV, Durham PL (2008) Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res 1196:22–32. https://doi.org/10.1016/j.brainres.2007.12.028
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 93:3455–3460
Luttrell LM et al (1999) Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 283:655–661
Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–545. https://doi.org/10.1038/nature05544
Macpherson LJ, Geierstanger BH, Viswanath V, Bandell M, Eid SR, Hwang S, Patapoutian A (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol 15:929–934. https://doi.org/10.1016/j.cub.2005.04.018
Main MJ, Brown J, Brown S, Fraser NJ, Foord SM (1998) The CGRP receptor can couple via pertussis toxin sensitive and insensitive G proteins. FEBS Lett 441:6–10
Marchese A, Benovic JL (2001) Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. J Biol Chem 276:45509–45512. https://doi.org/10.1074/jbc.C100527200
McLatchie LM et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339. https://doi.org/10.1038/30666
McNamara CR et al (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A 104:13525–13530. https://doi.org/10.1073/pnas.0705924104
McNeish AJ, Roux BT, Aylett SB, Van Den Brink AM, Cottrell GS (2012) Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries. Br J Pharmacol 167:1679–1690. https://doi.org/10.1111/j.1476-5381.2012.02129.x
Meens MJ, Compeer MG, Hackeng TM, van Zandvoort MA, Janssen BJ, De Mey JG (2010) Stimuli of sensory-motor nerves terminate arterial contractile effects of endothelin-1 by CGRP and dissociation of ET-1/ET(A)-receptor complexes. PLoS One 5:e10917. https://doi.org/10.1371/journal.pone.0010917
Meens MJ, Fazzi GE, van Zandvoort MA, De Mey JG (2009) Calcitonin gene-related peptide selectively relaxes contractile responses to endothelin-1 in rat mesenteric resistance arteries. J Pharmacol Exp Ther 331:87–95. https://doi.org/10.1124/jpet.109.155143
Meens MJ, Mattheij NJ, Nelissen J, Lemkens P, Compeer MG, Janssen BJ, De Mey JG (2011) Calcitonin gene-related peptide terminates long-lasting vasopressor responses to endothelin 1 in vivo. Hypertension 58:99–106. https://doi.org/10.1161/HYPERTENSIONAHA.110.169128
Meens MJ et al (2012) G-protein betagamma subunits in vasorelaxing and anti-endothelinergic effects of calcitonin gene-related peptide. Br J Pharmacol 166:297–308. https://doi.org/10.1111/j.1476-5381.2011.01774.x
Miller S, Liu H, Warfvinge K, Shi L, Dovlatyan M, Xu C, Edvinsson L (2016) Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies. Neuroscience 328:165–183. https://doi.org/10.1016/j.neuroscience.2016.04.046
Miron VE (2017) Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination. J Leukoc Biol 101:1103–1108. https://doi.org/10.1189/jlb.3RI1116-494R
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 36:22–33
Moreno MJ, Cohen Z, Stanimirovic DB, Hamel E (1999) Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture. J Cereb Blood Flow Metab 19:1270–1278. https://doi.org/10.1097/00004647-199911000-00012
Nakamichi K, Ihara M, Kobayashi M, Saeki T, Ishikawa K, Yano M (1992) Different distribution of endothelin receptor subtypes in pulmonary tissues revealed by the novel selective ligands BQ-123 and [Ala1,3,11,15]ET-1. Biochem Biophys Res Commun 182:144–150
Nikitenko LL, Blucher N, Fox SB, Bicknell R, Smith DM, Rees MC (2006) Adrenomedullin and CGRP interact with endogenous calcitonin-receptor-like receptor in endothelial cells and induce its desensitisation by different mechanisms. J Cell Sci 119:910–922. https://doi.org/10.1242/jcs.02783
O’Brien RF, Robbins RJ, McMurtry IF (1987) Endothelial cells in culture produce a vasoconstrictor substance. J Cell Physiol 132:263–270. https://doi.org/10.1002/jcp.1041320210
Oakley RH, Laporte SA, Holt JA, Caron MG, Barak LS (2000) Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors. J Biol Chem 275:17201–17210. https://doi.org/10.1074/jbc.M910348199
Obeid R, Herrmann W (2006) Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 580:2994–3005. https://doi.org/10.1016/j.febslet.2006.04.088
Olesen J et al (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110. https://doi.org/10.1056/NEJMoa030505
Oliver KR, Wainwright A, Edvinsson L, Pickard JD, Hill RG (2002) Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature. J Cereb Blood Flow Metab 22:620–629. https://doi.org/10.1097/00004647-200205000-00014
Ottosson A, Edvinsson L (1997) Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide. Cephalalgia 17:166–174. https://doi.org/10.1046/j.1468-2982.1997.1703166.x
Padilla BE, Cottrell GS, Roosterman D, Pikios S, Muller L, Steinhoff M, Bunnett NW (2007) Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins. J Cell Biol 179:981–997. https://doi.org/10.1083/jcb.200704053
Parameswaran N, Disa J, Spielman WS, Brooks DP, Nambi P, Aiyar N (2000) Activation of multiple mitogen-activated protein kinases by recombinant calcitonin gene-related peptide receptor. Eur J Pharmacol 389:125–130
Permpoonputtana K, Porter JE, Govitrapong P (2016) Calcitonin gene-related peptide mediates an inflammatory response in Schwann cells via cAMP-dependent ERK signaling cascade. Life Sci 144:19–25. https://doi.org/10.1016/j.lfs.2015.11.015
Peterson YK, Luttrell LM (2017) The diverse roles of arrestin scaffolds in G protein-coupled receptor signaling. Pharmacol Rev 69:256–297. https://doi.org/10.1124/pr.116.013367
Pezet S, McMahon SB (2006) Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 29:507–538. https://doi.org/10.1146/annurev.neuro.29.051605.112929
Prado MA, Evans-Bain B, Oliver KR, Dickerson IM (2001) The role of the CGRP-receptor component protein (RCP) in adrenomedullin receptor signal transduction. Peptides 22:1773–1781
Rajendran L et al (2008) Efficient inhibition of the Alzheimer’s disease beta-secretase by membrane targeting. Science 320:520–523. https://doi.org/10.1126/science.1156609
Ramesh G (2014) Novel therapeutic targets in neuroinflammation and neuropathic pain. Inflamm Cell Signal 1. https://doi.org/10.14800/ics.111
Rosciglione S, Theriault C, Boily MO, Paquette M, Lavoie C (2014) Galphas regulates the post-endocytic sorting of G protein-coupled receptors. Nat Commun 5:4556. https://doi.org/10.1038/ncomms5556
Russell FD, Skepper JN, Davenport AP (1997) Detection of endothelin receptors in human coronary artery vascular smooth muscle cells but not endothelial cells by using electron microscope autoradiography. J Cardiovasc Pharmacol 29:820–826
Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T (1990) Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348:732–735. https://doi.org/10.1038/348732a0
Sassone-Corsi P, Visvader J, Ferland L, Mellon PL, Verma IM (1988) Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. Genes Dev 2:1529–1538
Schaeffer C, Thomassin L, Rochette L, Connat JL (2003a) Apoptosis induced in vascular smooth muscle cells by oxidative stress is partly prevented by pretreatment with CGRP. Ann N Y Acad Sci 1010:733–737
Schaeffer C, Vandroux D, Thomassin L, Athias P, Rochette L, Connat JL (2003b) Calcitonin gene-related peptide partly protects cultured smooth muscle cells from apoptosis induced by an oxidative stress via activation of ERK1/2 MAPK. Biochim Biophys Acta 1643:65–73
Schafer C, Steffen H, Printz H, Goke B (1994) Effects of synthetic cyclic AMP analogs on amylase exocytosis from rat pancreatic acini. Can J Physiol Pharmacol 72:1138–1147
Scherer EQ, Herzog M, Wangemann P (2002) Endothelin-1-induced vasospasms of spiral modiolar artery are mediated by rho-kinase-induced Ca(2+) sensitization of contractile apparatus and reversed by calcitonin gene-related peptide. Stroke 33:2965–2971
Schlesinger DH, Goldstein G, Niall HD (1975) The complete amino acid sequence of ubiquitin, an adenylate cyclase stimulating polypeptide probably universal in living cells. Biochemistry 14:2214–2218
Seifert H, Sawchenko P, Chesnut J, Rivier J, Vale W, Pandol SJ (1985) Receptor for calcitonin gene-related peptide: binding to exocrine pancreas mediates biological actions. Am J Physiol 249:G147–G151. https://doi.org/10.1152/ajpgi.1985.249.1.G147
Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307–1313. https://doi.org/10.1126/science.1063866
Shih SC, Katzmann DJ, Schnell JD, Sutanto M, Emr SD, Hicke L (2002) Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis. Nat Cell Biol 4:389–393. https://doi.org/10.1038/ncb790
Simonetti M, Giniatullin R, Fabbretti E (2008) Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J Biol Chem 283:18743–18752. https://doi.org/10.1074/jbc.M800296200
Smillie SJ, Brain SD (2011) Calcitonin gene-related peptide (CGRP) and its role in hypertension. Neuropeptides 45:93–104. https://doi.org/10.1016/j.npep.2010.12.002
Sposini S, Hanyaloglu AC (2017) Spatial encryption of G protein-coupled receptor signaling in endosomes; mechanisms and applications. Biochem Pharmacol 143:1–9. https://doi.org/10.1016/j.bcp.2017.04.028
Storer RJ, Akerman S, Goadsby PJ (2004) Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 142:1171–1181. https://doi.org/10.1038/sj.bjp.0705807
Story GM et al (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829
Szymanska E, Budick-Harmelin N, Miaczynska M (2018) Endosomal “sort” of signaling control: the role of ESCRT machinery in regulation of receptor-mediated signaling pathways. Semin Cell Dev Biol 74:11–20. https://doi.org/10.1016/j.semcdb.2017.08.012
Takami K, Hashimoto K, Uchida S, Tohyama M, Yoshida H (1986) Effect of calcitonin gene-related peptide on the cyclic AMP level of isolated mouse diaphragm. Jpn J Pharmacol 42:345–350
Takamori M, Yoshikawa H (1989) Effect of calcitonin gene-related peptide on skeletal muscle via specific binding site and G protein. J Neurol Sci 90:99–109
Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A (2005) The role of mast cells in migraine pathophysiology. Brain Res Brain Res Rev 49:65–76. https://doi.org/10.1016/j.brainresrev.2004.11.006
Thomsen ARB et al (2016) GPCR-G protein-beta-arrestin super-complex mediates sustained G protein signaling. Cell 166:907–919. https://doi.org/10.1016/j.cell.2016.07.004
Trevisani M et al (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 104:13519–13524. https://doi.org/10.1073/pnas.0705923104
Tsvetanova NG, Irannejad R, von Zastrow M (2015) G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins from endosomes. J Biol Chem 290:6689–6696. https://doi.org/10.1074/jbc.R114.617951
Urbe S et al (2003) The UIM domain of Hrs couples receptor sorting to vesicle formation. J Cell Sci 116:4169–4179. https://doi.org/10.1242/jcs.00723
Van Dyke RW (2004) Heterotrimeric G protein subunits are located on rat liver endosomes. BMC Physiol 4:1. https://doi.org/10.1186/1472-6793-4-1
Van Valen F, Piechot G, Jurgens H (1990) Calcitonin gene-related peptide (CGRP) receptors are linked to cyclic adenosine monophosphate production in SK-N-MC human neuroblastoma cells. Neurosci Lett 119:195–198
Vause CV, Durham PL (2009) CGRP stimulation of iNOS and NO release from trigeminal ganglion glial cells involves mitogen-activated protein kinase pathways. J Neurochem 110:811–821. https://doi.org/10.1111/j.1471-4159.2009.06154.x
Vause CV, Durham PL (2010) Calcitonin gene-related peptide differentially regulates gene and protein expression in trigeminal glia cells: findings from array analysis. Neurosci Lett 473:163–167. https://doi.org/10.1016/j.neulet.2010.01.074
Walker CS et al (2015) A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol 2:595–608. https://doi.org/10.1002/acn3.197
Walker CS, Raddant AC, Woolley MJ, Russo AF, Hay DL (2017) CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. Cephalalgia:333102417691762. https://doi.org/10.1177/0333102417691762
Wendel-Wellner M, Noll T, Konig P, Schmeck J, Koch T, Kummer W (2002) Cellular localization of the endothelin receptor subtypes ET(A) and ET(B) in the rat heart and their differential expression in coronary arteries, veins, and capillaries. Histochem Cell Biol 118:361–369. https://doi.org/10.1007/s00418-002-0457-4
Weston C et al (2016) Receptor activity-modifying protein-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors. J Biol Chem 291:21925–21944. https://doi.org/10.1074/jbc.M116.751362
Wilkinson KD (2005) The discovery of ubiquitin-dependent proteolysis. Proc Natl Acad Sci U S A 102:15280–15282. https://doi.org/10.1073/pnas.0504842102
Wu Y et al (2015) Lentivirus mediated over expression of CGRP inhibited oxidative stress in Schwann cell line. Neurosci Lett 598:52–58. https://doi.org/10.1016/j.neulet.2015.05.009
Yanagisawa M et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415. https://doi.org/10.1038/332411a0
Yarwood RE et al (2017) Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission. Proc Natl Acad Sci U S A 114:12309–12314. https://doi.org/10.1073/pnas.1706656114
Zhang J, Ferguson SS, Barak LS, Menard L, Caron MG (1996) Dynamin and beta-arrestin reveal distinct mechanisms for G protein-coupled receptor internalization. J Biol Chem 271:18302–18305
Zhang Z, Winborn CS, Marquez de Prado B, Russo AF (2007) Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci 27:2693–2703. https://doi.org/10.1523/JNEUROSCI.4542-06.2007
Zhou Z, Hu CP, Wang CJ, Li TT, Peng J, Li YJ (2010) Calcitonin gene-related peptide inhibits angiotensin II-induced endothelial progenitor cells senescence through up-regulation of klotho expression. Atherosclerosis 213:92–101. https://doi.org/10.1016/j.atherosclerosis.2010.08.050
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Cottrell, G.S. (2018). CGRP Receptor Signalling Pathways. 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_130
Download citation
DOI: https://doi.org/10.1007/164_2018_130
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-21453-1
Online ISBN: 978-3-030-21454-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)