Modulation of GABA(C) Response by Ca(2+) 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 μM GABA was applied. The amplitude of I(GABA) increased as the extracellular Ca(2+) ([Ca(2+)](o)) was increased. Concentration–response curves of I(GABA) at 2.5 and 10 mM [Ca(2+)](o) had similar EC(50) (3.0 and 3.1 μM) and Hill coefficients (1.54 and 1.24). However, the maximal response estimated at 10 mM [Ca(2+)](o) was larger than the maximal response at 2.5 mM [Ca(2+)](o). Increasing Ca influx through voltage-gated Ca channels and the resulting rise in the intracellular Ca(2+) concentration had no effects on I(GABA). However, I(GABA) was inhibited by extracellular divalent cations, with the following order of the inhibitory potency: Zn(2+) > Ni(2+) > Cd(2+) > Co(2+). The inhibitory action of Zn(2+) on the [Ca(2+)](o)-dependent I(GABA) increase was noncompetitive. The action of [Ca(2+)](o) on I(GABA) was mimicked by Ba(2+) or Sr(2+). These results demonstrate that the extracellular domain of GABA(C) receptors has two functionally distinct binding sites represented by Ca(2+) (facilitation) and Zn(2+) (inhibition). Since [Ca(2+)](o) and [Zn(2+)](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.