Vasoactive intestinal polypeptide (VIP) has been shown to potentiate current responses elicited by activation of the GABAA receptor (IGABA) 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 (Gs)
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 IGABA, while
GDP beta s either decreased or had no effect on IGABA. Additionally,
GDP beta s blocked the potentiation of IGABA by VIP.
Cholera toxin rendered VIP ineffective in potentiating IGABA, while
pertussis toxin had no effect on the VIP-induced potentiation of IGABA. Extracellular application of either
forskolin or 8-bromo-cyclic
AMP potentiated IGABA, 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 IGABA, 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 GABAA receptor function by VIP in retinal ganglion cells.