VASOACTIVE-INTESTINAL-PEPTIDE STIMULATES NEUROPEPTIDE-Y GENE-EXPRESSION AND CAUSES NEURITE EXTENSION IN PC12 CELLS THROUGH INDEPENDENT MECHANISMS

Vasoactive intestinal peptide (VIP) is widely recognized as a regulato r of tyrosine hydroxylase via a mechanism of transsynaptic activation. Subsets of adrenal medullary cells and postganglionic sympathetic ner ves coexpress the peptide neurotransmitter neuropeptide Y (NPY) with c atecholamines. Using PC 12 cells transiently expressing a fusion gene in which the bacterial enzyme chloramphenicol acetyltransferase (CAT) is under the control of 700 base pairs of the 5' flanking region of th e NPY gene, we have studied the role of VIP and the related peptide pi tuitary adenylate cyclase activating peptide (PACAP) in regulating NPY gene transcription. Both VIP and PACAP stimulated expression of the N PY gene through activation of cAMP-dependent protein kinase. PACAP was 1000-fold more potent in eliciting this response compared to VIP and activity resided in its N-terminal 27 amino acids. Both VIP and PACAP caused a subpopulation (similar to 50%) of PC12 cells to undergo profo und morphological changes in that the cells extended long, slender neu rites with prominent growth cones. This change in morphology was unaff ected by preincubating cells with inhibitors of either cAMP-dependent protein kinase or calcium/phospholipid-dependent protein kinase. A tro phic role for either VIP or PACAP in regulating sympathetic nerve func tion is proposed.