Impact of CGRP receptor signaling on migraine pathophysiology
It is well established that calcitonin gene-related peptide (CGRP) receptor signaling plays a key role in migraine pathophysiology.1,2 Explore the sections below to find out more.
CGRP is a 37-amino-acid neuropeptide.2 It is a member of the calcitonin family of peptides that also includes amylin (AMY), adrenomedullin (ADM), and calcitonin.3,4
Clinical evidence suggests that CGRP may play a causal role in migraine, for example:5-7
Lassen LH, et al, Cephalalgia (vol 22, issue 1), pp 54-61, copyright © 2002 by SAGE Publications. Reprinted by permission of SAGE Publications, Ltd
Members of the calcitonin family of peptides bind to transmembrane-bound, G-protein-coupled receptors (GPCRs), commonly referred to as the calcitonin family of receptors.1
Each receptor is a heterodimer consisting of a receptor-activity-modifying protein (RAMP) and either the calcitonin receptor (CTR) or calcitonin receptor-like receptor (CLR) GPCR signaling subunit.1
CGRP-Rs are found in multiple areas involved in migraine pathophysiology, including the trigeminal ganglion (TG), cerebral and meningeal vasculature, the trigeminal nucleus caudalis (TNC) of the brainstem, and regions of the brain such as the thalamus.8-10 They are also expressed on numerous cell types such as vascular smooth muscle cells, neurons, glial cells, and mast cells.8-12
Of the calcitonin receptors, only the CGRP receptor (CGRP-R) has been implicated in migraine pathophysiology.1 The role of the other receptors in migraine pathophysiology is currently unknown.1
CGRP–CGRP-R signaling regulates key events that underlie migraine pathophysiology, including trigeminovascular neuron sensitization and neuropeptide release.2,13
The complex role of CGRP–CGRP-R signaling in migraine pathophysiology may involve multiple processes in both the central and peripheral nervous systems, including:8,10,14-17
- Vasodilation8,10,14-16
- Nociceptor activation (peripheral)8,10,14-16
- Neurogenic inflammation8,10,14-16
- Central sensitization14,15
- Cortical spreading depression10,14,16
- Central trigeminal sensory activation8,14,15
- Hypothalamic dysfunction and descending control of brainstem structures14,17
In addition to binding to CGRP-R, CGRP has high affinity for another calcitonin receptor, the amylin 1 receptor (AMY1-R).1,3 These two receptors have the RAMP1 subunit in common.1
CGRP and CGRP-R are expressed in various tissues in the body.2,11,19–23 CGRP signaling through CGRP-R has several firmly established physiologic roles, including nociception, sensory modulation, and vasodilation.2
The main source of amylin (AMY) ligand is the pancreatic beta cells, and AMY1-R is expressed in the vasculature and the trigeminal ganglion (TG).3,24–26
Various roles for AMY1-R have been suggested as a result of its location and the expression pattern of its ligands.4,25,26 AMY-1 signalling through AMY1-R has well-established physiologic roles in regulating postprandial glucose levels, glycemic control, and satiation.25,26
