Modulation by Zn²⁺ and Cd²⁺ of GABA_A receptors of rat cerebellum granule cells in culture

Abstract.

This study aims to characterize more closely the different populations of GABA_A receptors present on the cerebellar granule cells of the rat. The effects of two divalent cations, Zn²⁺ and Cd²⁺, on GABA-activated chloride currents were studied using the whole-cell patch-clamp technique. Zinc cations inhibit differently the peak and the steady-state current elicited by 10 µM GABA. In fact, Zn²⁺ appears to be more potent in inhibiting the steady-state component, with a lower IC₅₀. The inhibition of the peak component is of the competitive type, whereas the inhibition of the steady-state one is mixed, being partly competitive and partly allosteric. In addition, Cd²⁺ has an inhibitory effect on GABA-activated chloride currents. In terms of the peak component, its effect is limited in extent with a maximal inhibition of only 26%, but with a high affinity (IC₅₀ as low as 0.03 µM). The steady-state component is inhibited by 20% independently from the Cd²⁺ concentration, in the 10^–2–10² µM range. In this case, the inhibitory mechanism appears to be of the competitive type for the peak component and of the allosteric type for the steady-state one. We suggest these data are a further confirmation that the rapidly and slowly desensitizing components of the GABA-activated chloride currents, corresponding respectively to the peak and the steady-state components, are made up of two different receptor populations.