VASOACTIVE INTESTINAL POLYPEPTIDE MODULATES GABA(A) RECEPTOR FUNCTION THROUGH ACTIVATION OF CYCLIC-AMP

Vasoactive intestinal polypeptide (VIP) has been shown to potentiate current responses elicited by activation of the GABA(A) receptor (I-GABA) in freshly dissociated ganglion cells of the rat retina. Here we tested the hypothesis that this heteroreceptor cross talk is mediated by an intracellular cascade of events that includes the sequential activation of a stimulatory guanine nucleotide binding (G(s)) protein and adenylate cyclase, the subsequent increase in levels of cyclic AMP and, finally, the action of the cyclic AMP-dependent protein kinase (PKA). Intracellular dialysis of freshly dissociated ganglion cells with GTP gamma s irreversibly potentiated I-GABA, while GDP beta s either decreased or had no effect on I-GABA Additionally, GDP beta s blocked the potentiation of I-GABA by VIP. Cholera toxin rendered VIP ineffective in potentiating I-GABA, while pertussis toxin had no effect on the VIP-induced potentiation of I-GABA. Extracellular application of either forskolin or 8-bromo-cyclic AMP potentiated I-GABA, as did the introduction of cyclic AMP directly into the intracellular compartment through the recording pipet. Intracellular application of cyclic AMP-dependent protein kinase (PKA) potentiated I-GABA, while a PKA inhibitor blocked the potentiating effect of VIP. These results lead us to conclude that activation of a cyclic AMP-dependent second-messenger system mediates the modulation of GABA(A) receptor function by VIP in retinal ganglion cells.