Modulation of GABA(C) response by Ca2+ and other divalent cations in horizontal cells of the catfish retina

GABA(C) responses were recorded in cultured cone-driven horizontal cells from the catfish retina using the patch clamp technique, At a holding potential of -49 mV, a bicuculline-resistant inward current (I-GABA) was observed when 10 mu M GABA was applied. The amplitude of I-GABA increased as the extracellular Ca2+ ([Ca2+](o)) was increased. Concentration-response curves of I-GABA at 2.5 and 10 mM [Ca2+](o) had similar EC50 (3.0 and 3.1 mu M) and Hill coefficients (1.54 and 1.24). However, the maximal response estimated at 10 mM [Ca2+](o) was larger than the maximal response at 2.5 mM [Ca2+](o). Increasing Ca influx through voltage-gated Ca channels and the resulting rise in the intracellular Ca2+ concentration had no effects on I-GABA. However, I-GABA was inhibited by extracellular divalent cations, with the following order of the inhibitory potency: Zn2+ > Ni2+ > Cd2+ > Co2+. The inhibitory action of Zn2+ on the [Ca2+](o)-dependent I-GABA increase was noncompetitive. The action of [Ca2+](o) on I-GABA was mimicked by Ba2+ or Sr2+. These results demonstrate that the extracellular domain of GABA(C) receptors has two functionally distinct binding sites represented by Ca2+ (facilitation) and Zn2+ (inhibition). Since [Ca2+](o) and [Zn2+](o) change into the opposite direction by light, it seems likely that they modify cooperatively the efficacy of the positive feedback consisting of the GABA(C) receptor.