GABA receptors of bipolar cells from the skate retina: Actions of zinc on GABA-mediated membrane currents

gamma-Aminobutyric acid (GABA)-induced currents were recorded from isolated bipolar cells of the skate retina using perforated patch-clamp methodology. Pharmacological analysis of the responses, using selective agonists and antagonists of the major classes of GABA receptor, revealed the presence of both GABA(A) and GABA(C) receptors at both the dendrites and axon terminals of the bipolar cells. The two receptor types showed very different reactions to zinc, a divalent metallic cation that was detected in the synaptic terminal region of skate photoreceptors. Currents mediated by the activation of GABA(C) receptors were down-regulated by zinc, a feature that is typical of the action of zinc on GABA(C) receptors. On the other hand, the effects of zinc on GABA(A) receptor-mediated activity was highly dependent on zinc concentration. Unlike the GABA(A) receptors on other neurons, responses mediated by activation of the GABA(A) receptor of skate bipolar cells were significantly enhanced by zinc concentrations in the range of 0.1-100 mu M; at higher concentrations of zinc (>100 mu M), response amplitudes were suppressed below control levels. The enhancement of GABA(A) receptor activity on skate bipolar cells showed little voltage dependence, suggesting that zinc is acting on the extracellular domain of the GABA(A) receptor. In the presence of 10 mu M zinc, the dose-response curve for 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; a GABA(A) agonist that suppresses GABA(C)-activated currents) was shifted to the left of the curve obtained in the absence of zinc, but without a significant change in the response maximum. This finding indicates that the enhancing effect of zinc is due primarily to its ability to increase the sensitivity of the GABA(A) receptor. The novel enhancement of neuronal GABA(A) receptor activity by zinc, observed previously in the GABA(A)-mediated responses of skate Muller (glial) cells, may reflect the presence of a unique subtype of GABA(A) receptor on the bipolar and Muller cells of the skate retina.