Neuroanatomical Localization, Pharmacological Characterization and Functions of CGRP, Related Peptides and Their Receptors

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Abstract

VAN ROSSUM, D. U.-K. HANISCH AND R. QUIRION. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. NEUROSCI BIOBEHAV REV 21(5)649–678, 1997.—Calcitonin gene-related peptide (CGRP) is a neuropeptide discovered by a molecular approach over 10 years ago. More recently, islet amyloid polypeptide or amylin, and adrenomedullin were isolated from human insulinoma and pheochromocytoma respectively, and revealed between 25 and 50% sequence homology with CGRP. This review discusses findings on the anatomical distributions of CGRP mRNA, CGRP-like immunoreactivity and receptors in the central nervous system, as well as the potential physiological roles for CGRP. The anatomical distribution and biological activities of amylin and adrenomedullin are also presented. Based upon the differential biological activity of various CGRP analogs, the CGRP receptors have been classified in two major classes, namely the CGRP1 and CGRP2 subtypes. A third subtype has also been proposed (e.g. in the nucleus accumbens) as it does not share the pharmacological properties of the other two classes. The anatomical distribution and the pharmacological characteristics of amylin binding sites in the rat brain are different from those reported for CGRP but share several similarities with the salmon calcitonin receptors. The receptors identified thus far for CGRP and related peptides belong to the G protein-coupled receptor superfamily. Indeed, modulation of adenylate cyclase activity following receptor activation has been reported for CGRP, amylin and adrenomedullin. Furthermore, the binding affinity of CGRP and related peptides is modulated by nucleotides such as GTP. The cloning of various calcitonin and most recently of CGRP1 and adrenomedullin receptors was reported and revealed structural similarities but also significant differences to other members of the G protein-coupled receptors. They may thus form a new subfamily. The cloning of the amylin receptor(s) as well as of the other putative CGRP receptor subtype(s) are still awaited. Finally, a broad variety of biological activities has been described for CGRP-like peptides. These include vasodilation, nociception, glucose uptake and the stimulation of glycolysis in skeletal muscles. These effects may thus suggest their potential role and therapeutic applications in migraine, subarachnoid haemorrhage, diabetes and pain-related mechanisms, among other disorders. © 1997 Elsevier Science Ltd.

Section snippets

INTRODUCTION

CALCITONIN gene-related peptide (CGRP) is a 37 amino acid peptide generated from the alternative splicing of the calcitonin gene. Two forms have thus far been isolated, namely CGRPα and CGRPβ (also called CGRP-I and CGRP-II). CGRP shares about 25% sequence homology with calcitonin and adrenomedullin and about 50% with amylin. Since the discovery of CGRP, several groups have reported on the presence of CGRP mRNA as well as of CGRP-like immunoreactivity in both central and peripheral nervous

NEUROANATOMICAL LOCALIZATION

CGRP is one of the most broadly distributed peptides in nerve tissues in both vertebrates and invertebrates. The detailed map of the discrete distribution of CGRP mRNA, CGRP immunoreactive cell bodies and nerve fibers have been reported in various species, including rat, cat and human brains, and is summarized in the following sections.

Distribution of CGRP receptor sites in the brain

Several studies have demonstrated the anatomically discrete distribution of binding sites for CGRP in the central nervous system of various species, including rat and human 135, 150, 192, 349. These binding sites have a characteristic distribution (Fig. 3YA, Fig. 3YB, Fig. 3YC, third column) which is distinct from those previously reported for other neuropeptide receptors.

High levels of [125I]hCGRP binding have been reported in the nucleus accumbens, ventral striatum and tail of the caudate

CGRP

Activation of adenylate cyclase and/or increases in intracellular cAMP induced by CGRP have been reported in many tissue preparations including rat liver [386], rat and guinea pig heart cells 93, 157, 371, rat skeletal muscle [10], rat astrocytic culture [201] and human neuroblastoma and gliomas 291, 361. The relaxant effects of CGRP on various smooth muscle preparations such as rat thoracic and abdominal aorta 91, 126, 372, rat intracerebral arterioles [80], porcine coronary arteries [170] as

Fiber pathways containing CGRP

CGRP-immunoreactive structures are widely distributed in the brain, which suggests the possible involvement of this peptide in various brain functions, especially in specific sensory, motor and integrative systems. The main CGRP pathways are described in the following sections and summarized in Fig. 4. For an extensive review on immunohistochemical localization and functional aspects of CGRP in peripheral sensory branches, see Ishida-Yamamoto and Tohyama [154].

CONCLUSION AND PERSPECTIVE

CGRP and related peptides possess a broad variety of biological effects possibly mediated by various specific receptor subtypes. Surprisingly, limited data are thus far available with respect to the molecular characteristics and topography of the respective receptors. Clearly, the ultimate pharmacological characterization of these receptor classes will follow their isolation, purification and cloning. Success is now apparent through this approach, as most recently few forms of the receptors

NOTE ADDED IN PROOF

Following the acceptance of the present manuscript, we became aware of a report on the cloning of a novel protein that interacts with CGRP (Luebke, A.E.; Dahl, G.P.; Roos, B.A.; Dickerson, I.M. Proc. Natl. Acad. Sci. USA, in press). This small (146 amino acids), largely hydrophilic protein is believed to be either a CGRP receptor or a component of a CGRP receptor complex. This novel protein does not belong to the typical seven transmembrane domains G protein-coupled receptor superfamily, as it

Acknowledgements

This research is supported by the Medical Research Council of Canada (MRCC). DvR is an awardee of the MRCC and of the Human Frontier Science Program Organisation (HFSPO). RQ is Chercheur Boursier from Fonds de la Recherche en Santé du Québec. The authors also wish to thank Dr. Daniel P. Ménard for numerous helpful discussions.

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