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The Journal of Neuroscience, August 1, 1999, 19(15):6327-6337

Pituitary Adenylate Cyclase-Activating Polypeptide Activates a Phospholipase C-Dependent Signal Pathway in Chick Ciliary Ganglion Neurons that Selectively Inhibits 7-Containing Nicotinic Receptors

Desiree Pardi and Joseph F. Margiotta

Department of Anatomy and Neurobiology, Medical College of Ohio, Toledo, Ohio 43614-5804

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, -bungarotoxin (Bgt)-sensitive 7-AChRs and the slowly desensitizing, Bgt-insensitive 3*-AChRs on the neurons were potentiated by PACAP. After AC blockade, however, PACAP inhibited 7-AChRs but left 3*-AChRs unaffected. The selective inhibition of 7-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.

Key words: neuropeptide; acetylcholine; ion channel; modulation; fast perfusion; Ca²⁺ imaging; whole-cell recording

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19156327-11$05.00/0

This article has been cited by other articles:

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