Pituitary adenylate cyclase-activating polypeptide regulation of vasoactive intestinal polypeptide transcription requires Ca2+ influx and activation of the serine/threonine phosphatase calcineurin

A >15-fold increase in vasoactive intestinal polypeptide (VIP) mRNA and VIP peptide levels occurred in primary chromaffin cells following exposure to the neurotrophic neuropeptide pituitary adenylate cyclase-activating polype ptide (PACAP)-27 with an EC50 of similar to 2 nM. PACAP induction of VIP ex pression was blocked by methoxyverapamil or by a combination of nimodipine and omega-conotoxin MVIIC, indicating a requirement for PACAP-initiated cal cium entry through voltage-dependent calcium channels for regulation of VIP biosynthesis. Ascomycin, which inhibits calcineurin through formation of a n ascomycin/FKBP12/calcineurin ternary complex, abolished the PACAP-evoked increase in VIP expression, whereas rapamycin, which also binds to FKBP12 b ut does not cause inhibition of calcineurin, did not. Cyclosporin A, which inhibits calcineurin through formation of a cyclosporin A/cyclophilin/calci neurin complex, also abolished PACAP-evoked VIP biosynthesis, These data in dicate that PACAP regulates the expression of VIP via a signaling pathway t hat requires calcium influx and activation of calcineurin.