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

Vasoactive intestinal peptide receptor 1 (VPAC1) and vasoactive intestinal peptide receptor 2 (VPAC2) are class B G protein-coupled receptors that bind vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) with high affinity. Both receptors are widely expressed in the central and peripheral nervous systems, as well as in peripheral tissues including the gastrointestinal tract and immune system. Their activation primarily stimulates adenylyl cyclase via the Gs protein, increasing cAMP levels and leading to a variety of cellular responses: regulation of secretion, hormone release, immune cell function, and neuroprotection. They play roles in inflammation, neurodegeneration, cancer, and cardiovascular regulation, making them attractive—if challenging—drug targets. The design of selective VPAC1/VPAC2-targeted agents is difficult due to high homology with each other and with the related PAC1 receptor. Few clinical drugs exist, but select peptide agonists/antagonists and one reported negative allosteric modulator (ticagrelor) have shown experimental activity. Safety concerns stem from their broad tissue distribution and involvement in immune modulation[1][2][3][4][5][6][7][8].

Other names

Vasoactive intestinal peptide receptor 1 (VIPR1, VPAC1)Vasoactive intestinal peptide receptor 2 (VIPR2, VPAC2)Class B G protein-coupled receptor (subtype)Secretin family receptors (subfamily)VIP receptor 1/VIP1 (historical, now VPAC1)VIP receptor 2/VIP2 (historical, now VPAC2)PACAP (Pituitary adenylate cyclase-activating peptide) receptor (cross-reactive binding)

Agonists: Stimulate receptors to activate adenylyl cyclase and increase cAMP signaling Antagonists: Block peptide binding and suppress downstream GPCR signaling Allosteric modulators: Bind to non-orthosteric sites to modulate receptor activity, as seen with ticagrelor