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Neuropeptide receptors couple via G-proteins to two principal signaling pathways that elevate cAMP through adenylate cyclase (AC) or mobilize intracellular Ca2+ through phospholipase C (PLC)-stimulated inositol phosphate (IP) turnover and production of inositol 1,4,5-trisphosphate (IP3). We showed previously that high-affinity receptors for pituitary adenylate cyclase-activating polypeptide (PACAP) are present on chick ciliary ganglion neurons and that receptor occupation increases cAMP production, resulting in enhanced acetylcholine sensitivity. After we suppressed AC activity and cAMP production with 2′-5′ dideoxyadenosine, however, PACAP no longer increased acetylcholine sensitivity but instead reduced it, suggesting that an AC-independent signal pathway activated by PACAP inhibits some nicotinic acetylcholine receptors (AChRs). We now use fast-perfusion, imaging, and biochemical methods to identify the AChRs modulated by PACAP and to characterize the signal pathway responsible for their inhibition. Without previous AC block, both the rapidly desensitizing, α-bungarotoxin (αBgt)-sensitive α7-AChRs and the slowly desensitizing, αBgt-insensitive α3*-AChRs on the neurons were potentiated by PACAP. After AC blockade, however, PACAP inhibited α7-AChRs but left α3*-AChRs unaffected. The selective inhibition of α7-AChRs appeared to use a PLC signaling pathway because it was not seen after lowering PLC activity or buffering intracellular Ca2+ and was mimicked by dialyzing neurons with an IP3 receptor agonist. PACAP also induced IP turnover and increased [Ca2+]i assessed directly with Fluo-3AM imaging. Given our previous findings that PACAP receptors couple to AC, the present results demonstrate a remarkable ability of a single neuropeptide to activate two signaling pathways and in so doing selectively regulate two classes of downstream ion channel targets.

the journal of neuroscience/the journal of neuroscience

Pituitary Adenylate Cyclase-Activating Polypeptide Activates a Phospholipase C-Dependent Signal Pathway in Chick Ciliary Ganglion Neurons that Selectively Inhibits α7-Containing Nicotinic Receptors