CGRP: a Multifunctional Neuropeptide

Abstract

It has been just over 20 years since the neuropeptide calcitonin gene‐related peptide (CGRP) was unexpectedly discovered embedded within the calcitonin gene. Since then CGRP has emerged as a key regulator of multiple physiological and pathological functions. CGRP is expressed in a subset of neurons in the central and peripheral nervous system that innervate every major organ system. Within this context, CGRP is a multifunctional peptide that is a major modulator of the cardiovascular system and a key player in neurogenic inflammatory pain. Since the discovery of CGRP, a repertoire of related peptides have been identified. The expression patterns and activities of these family members are discussed briefly. We will focus on how CGRP gene transcription is controlled by extracellular signals that target the cell‐specific and cAMP‐regulated enhancers. An emphasis of the chapter will be the unusual mechanism by which the CGRP receptor requires the G‐protein‐coupled calcitonin‐like receptor (CLR), receptor activity modifying protein‐1 (RAMP1), and receptor component protein (RCP). We will then address the physiological activities of CGRP in the cardiovascular and smooth muscle, skeletal muscle, and cochlear systems. Finally, we will discuss two pathologies that involve CGRP in the trigeminovascular system: migraine and subarachnoid hemorrhage (SAH). The efficacy of a CGRP receptor antagonist has now established the importance of elevated CGRP in migraine. In contrast, the lack of CGRP may contribute to fatal vasospasms in SAH. Thus, the continuing development of pharmacological and genetic approaches for modulating CGRP expression and activity holds exciting promise for future therapeutic strategies.