Vasoactive intestinal peptide receptor 1 and vasoactive intestinal peptide receptor 2 (VPAC1 and VPAC2)

Vasoactive intestinal peptide receptor 1 (VPAC1) and vasoactive intestinal peptide receptor 2 (VPAC2) are G protein-coupled receptors that mediate the effects of VIP and PACAP, which are neuropeptides involved in numerous physiological processes such as smooth muscle relaxation, hormone secretion, immune regulation, and central nervous system signaling. VPAC1 is widely expressed across many tissues—including the liver, brain, immune cells—while VPAC2 is expressed primarily in the central nervous system and pancreatic islet cells. Both receptors couple to the Gs protein to stimulate cAMP, with VPAC1 also interacting with RAMP proteins and potentially influencing calcium signaling. These receptors are implicated as therapeutic targets for diseases ranging from asthma, cancer, diabetes, to neurodegeneration, yet challenges remain in drug development—including selectivity between subtypes, peptide stability, and avoidance of off-target effects.

Other names

VPAC1 receptorVPAC2 receptorVIP receptor 1VIP receptor 2Vasoactive intestinal peptide receptor type 1Vasoactive intestinal peptide receptor type 2VIPR1 (for VPAC1, less common)VIPR2 (for VPAC2, less common)

Agonists activate VPAC1 or VPAC2, stimulating cAMP production and downstream signaling (insulin secretion, inhibition of inflammation, smooth muscle relaxation). Antagonists inhibit VIP/PACAP-mediated receptor activation, suppressing cell proliferation and tumor growth, blocking anti-inflammatory actions, or reducing neuroprotective effects. Selective targeting of VPAC2 can stimulate glucose-dependent insulin secretion without hepatic glycogenolysis, making it a candidate for diabetes therapy.