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Keywords:

  • Vasoactive intestinal polypeptide;
  • Primary chromaffin cells;
  • Pituitary adenylate cyclase-ac-tivating polypeptide;
  • Calcium influx;
  • Calcineurin activation

Abstract : 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 polypeptide (PACAP)-27 with an EC50 of ~2 nM. PACAP induction of VIP expression was blocked by methoxyverapamil or by a combination of nimodipine and ω-conotoxin MVIIC, indicating a requirement for PACAP-initiated calcium entry through voltage-dependent calcium channels for regulation of VIP biosynthesis. Ascomycin, which inhibits calcineurin through formation of an ascomycin/FKBP12/calcineurin ternary complex, abolished the PACAP-evoked increase in VIP expression, whereas rapamycin, which also binds to FKBP12 but does not cause inhibition of calcineurin, did not. Cyclosporin A, which inhibits calcineurin through formation of a cyclosporin A/cyclophilin/calcineurin complex, also abolished PACAP-evoked VIP biosynthesis. These data indicate that PACAP regulates the expression of VIP via a signaling pathway that requires calcium influx and activation of calcineurin.