CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond

Abstract

Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. Its two isoforms (α and β) are widely expressed throughout the body in sensory neurons, as well as in other cell types, such as motor neurons and neuroendocrine cells. CGRP acts via at least two G protein-coupled receptors that form unusual complexes with receptor activity-modifying proteins. These are the CGRP receptor and the AMY1 receptor; in rodents, additional receptors come into play. Although CGRP is known to produce many effects, the precise molecular identity of the receptor(s) that mediate CGRP effects is seldom clear. Despite the many enigmas still in CGRP biology, therapeutics that target the CGRP axis to treat or prevent migraine are a bench to bedside success story. This review provides a contextual background on the regulation and sites of CGRP expression and CGRP receptor pharmacology. The physiological actions of CGRP in the nervous system are discussed, along with updates on CGRP actions in the cardiovascular, pulmonary, gastrointestinal, immune, hematopoietic, and reproductive systems, and metabolic effects of CGRP in muscle and adipose tissues. We cover how CGRP in these systems is associated with disease states, most notably migraine. In this context, we discuss how CGRP actions in both the peripheral and central nervous systems provide a basis for therapeutic targeting of CGRP in migraine. Finally, we highlight potentially fertile ground for the development of additional therapeutics and combinatorial strategies that could be designed to modulate CGRP signaling for migraine and other diseases.

Effectiveness of three calcitonin gene-related peptide monoclonal antibodies for migraine: A 12-month, single-center, observational real-world study in Japan

“…Central or peripheral CGRP levels increase in response to central (repeated cortical spreading depression) or peripheral signals (changes in the trigeminal vascular systems), resulting in peripheral and central sensitization, leading to sensory hypersensitivity, including osmophobia (28). The trigeminal nerves expressing CGRP project into the olfactory bulb, and olfactory sensory neurons, which project axons to the olfactory bulb, express CGRP receptors (29).…”

Management of cluster headache: Treatments and their mechanisms

“…Side effects for CGRP-mAbs are remarkably limited given the widespread functions of CGRP in multiple organ systems including cardiovascular, neurovascular, pulmonary, gastrointestinal, muscular, and immunologic (100). Common side effects from clinical trials were upper respiratory tract infections and injection site reactions.…”

“…While the mechanism of action is clear, the site of action of CGRP-mAbs is, in contrast, still under debate. CGRP receptors have been found in intracranial arteries, peripheral neurons, and central neurons (100). In fact, CGRP is the most abundant neuropeptide in the trigeminal ganglion (105).…”

“…The mechanism of action for CGRP-mAbs is thought to be clear, as these antibodies are highly specific for either the CGRP ligand (eptinezumab, fremanezumab, and galcanezumab) or for the CGRP receptor (erenumab). It should be noted, however, that CGRP ligand blockers may have different effects than CGRP receptor blockers for the following two reasons: 1) CGRP binds not only to the CGRP receptor but also to the amylin-1 receptor (100), and 2) a functional magnetic resonance study showed ligand- and receptor-specific activation of networks in patients receiving galcanezumab versus erenumab (104). While the mechanism of action is clear, the site of action of CGRP-mAbs is, in contrast, still under debate.…”

Pharmacological characterisation of erenumab, Aimovig, at two calcitonin gene‐related peptide responsive receptors

“…Calcitonin gene‐related peptide (CGRP) is a neuropeptide with many functions, such as being involved in the cardiovascular system and in metabolism (Russo & Hay, 2023). Strong evidence links CGRP to migraine.…”