VIP MODULATES NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR FUNCTION BY ACYCLIC-AMP-DEPENDENT MECHANISM

Neuronal nicotinic ACh receptors (AChRs) mediate synaptic transmission throughout the nervous system, and are regulated by cellular processe s and interactions that include second messenger signaling pathways. I n the case of chick ciliary ganglion neurons, activation of the cAMP-d ependent signaling pathway with cAMP analogs enhances ACh sensitivity in a manner consistent with an increase in the number of functional ni cotinic receptors. We have now identified vasoactive intestinal peptid e (VIP) as a neuromodulator or ''first messenger'' in the cAMP-mediate d pathway that regulates neuronal AChRs. Using cAMP imaging and bioche mical detection assays, we find that bath application of VIP elevates intracellular cAMP in freshly isolated ciliary ganglion neurons within minutes. The VIP treatment also enhances neuronal ACh sensitivity ass essed with whole-cell recording. The enhanced ACh sensitivity produced by VIP appears with a short latency, similar to that associated with the increase in cAMP, and is not additive with the enhanced ACh sensit ivity produced by bath application of a cAMP analog. In contrast, calc itonin gene-related peptide (CGRP), known to regulate muscle nicotinic AChRs via a cAMP-dependent pathway, has no detectable effect on level s of either cAMP or ACh sensitivity in the neurons. The results indica te that VIP enhances the ACh sensitivity of ciliary ganglion neurons v ia a cAMP-dependent signaling pathway, presumably by interaction with a specific receptor. Since VIP-like immunoreactivity is present in the presynaptic nerve terminals of avian ciliary ganglia, a VIP-like pept ide could modulate AChRs in vivo.