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

Vasoactive intestinal polypeptide (VIP) has been shown to potentiate c urrent responses elicited by activation of the GABA(A) receptor (I-GAB A) in freshly dissociated ganglion cells of the rat retina. Here we te sted the hypothesis that this heteroreceptor cross talk is mediated by an intracellular cascade of events that includes the sequential activ ation of a stimulatory guanine nucleotide binding (G(s)) protein and a denylate 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 decr eased 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 f orskolin or 8-bromo-cyclic AMP potentiated I-GABA, as did the introduc tion of cyclic AMP directly into the intracellular compartment through the recording pipet. Intracellular application of cyclic AMP-dependen t protein kinase (PKA) potentiated I-GABA, while a PKA inhibitor block ed the potentiating effect of VIP. These results lead us to conclude t hat activation of a cyclic AMP-dependent second-messenger system media tes the modulation of GABA(A) receptor function by VIP in retinal gang lion cells.