AlphaCGRP

Alpha calcitonin gene-related peptide (alphaCGRP) is a 37-amino-acid neuropeptide that functions as a major mediator of vasodilation and nociceptive signaling in the nervous system. In humans it is produced from the calcitonin gene CALCA by tissue-specific alternative splicing, making alphaCGRP the predominant CGRP form in the central and peripheral nervous systems. A related peptide, beta-CGRP, is encoded by CALCB and is expressed in different tissues such as the enteric nervous system.

Biogenesis and structure: CALCA is transcribed into prepro-CGRP, which is processed to the mature alphaCGRP peptide containing a C-terminal amide. AlphaCGRP exerts its effects by binding to the CGRP receptor, a heteromeric complex composed of the calcitonin receptor-like receptor (CALCRL), receptor activity-modifying protein 1 (RAMP1), and the membrane-associated protein CRCP, which together enable signaling. Receptor activation typically stimulates adenylate cyclase and increases intracellular cAMP in target cells.

Physiology and role in disease: AlphaCGRP is widely expressed in sensory neurons, including trigeminal and dorsal root ganglia neurons, and is released during neural activation. It promotes vasodilation of cranial and peripheral vessels, participates in neurogenic inflammation, and modulates pain signaling. The release of CGRP in the meninges is implicated in migraine pathophysiology, where vascular and inflammatory responses contribute to headache generation.

Clinical relevance: Therapeutic strategies targeting CGRP signaling include small-molecule antagonists (gepants) and monoclonal antibodies against CGRP or its receptor, approved for migraine prevention and treatment. These therapies aim to reduce migraine frequency and severity by inhibiting alphaCGRP signaling, with common adverse effects including injection-site reactions and constipation reported for some agents.