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