pituitary adenylate cyclase-activating polypeptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous neuropeptide hormone belonging to the vasoactive intestinal peptide (VIP)/secretin/glucagon family. It exists primarily in two isoforms—PACAP38 and the shorter PACAP27. Discovered in 1989 from ovine hypothalamic tissue, it is widely distributed throughout the central nervous system and peripheral organs such as lung, heart, gut, and testis[5][1]. PACAP acts mainly through three class B G protein-coupled receptors (GPCRs): the high-affinity PAC1 receptor and VPAC1/VPAC2 receptors. The neuroprotective and neurotrophic effects of PACAP are primarily mediated via the PAC1 receptor; activation of VPAC1 may mediate inflammatory responses while VPAC2 activation can cause vasodilation and water retention[5][2]. Mechanistically, upon binding to its receptors—especially the neuronal-specific splice variant of the PAC1 receptor—PACAP activates multiple intracellular signaling pathways including MAPK/ERK and PI3K/Akt cascades that promote neuronal survival after injury or stress[2]. In addition to its roles in development and repair within neural tissues, it regulates vascular tone by dilating blood vessels (notably cranial vessels), modulates sleep/circadian rhythms via hypothalamic action[7][5][1], influences immune/inflammatory mediator production[6], and has been implicated as a key mediator in migraine pathogenesis where exogenous administration can induce migraine-like headaches in susceptible individuals[6][3][7]. Currently there are no approved pharmaceutical products containing native or modified forms of PACAP; however investigational therapies targeting this pathway—including monoclonal antibodies against either the peptide or its main receptor—are under clinical evaluation for headache disorders such as migraine[4][3].

Other names

pituitary adenylate cyclase-activating peptidepituitary adenylate-cyclase-activating polypeptidePACAP 1–38PACAP 1–27