Pituitary adenylate-cyclase activating polypeptide (PACAP) evokes long-lasting secretion and de novo biosynthesis of bovine adrenal medullary neuropeptides.

Recently, the pituitary adenylate-cyclase activating polypeptide (PACAP) has emerged as a potential noncholinergic neuromodulator of adrenal medullary function. In support of this hypothesis, we documented PACAP's effects on the secretion and biosynthesis of neuropeptides by cultured bovine chromaffin cells. Data presented in this study indicate that PACAP is a potent and efficacious secretagogue of leucine-enkephalin which was coreleased with catecholamines with identical profiles. In comparison to nicotinic activation, however, rates of PACAP-induced secretion were substantially slower but persisted for several hours causing a prolonged increase in the tonic release of both transmitters and peptides. Interestingly, renewal of intracellular pools of neuropeptides was also stimulated by PACAP but not the vasoactive intestinal peptide (VIP). Indeed, the higher incorporation of [35S]-labeled amino acids into atrial and brain natriuretic peptides (ANP, BNP) provided strong evidence that PACAP directly activated de novo biosynthesis. Of particular importance was PACAP's net preferential stimulation of the biosynthesis of BNP, similar to the differential regulation by protein kinase A (PK-A) and protein kinase C (PK-C) activators we have previously the differential regulation by protein kinase A (PK-A) and protein kinase C (PK-C) activators we have previously reported. PACAP-induced secretion and biosynthesis appeared to be mediated by the PACAP-specific type I receptors known to activate adenylate cyclase and phospholipase C. We verified that PACAP did indeed stimulate the production of cyclic AMP and inositol phosphates in our cell system. These findings suggest that the dual signaling properties of type I receptors may be important for PACAP's differential effect on the biosynthesis of natriuretic peptides. We conclude that PACAP might assume important noncholinergic trans-synaptic regulation of the adrenal medulla by releasing and modifying intragranular catecholamine and neuropeptide contents.