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Interaction of H⁺ and Zn²⁺ on recombinant and native rat neuronal GABA_A receptors

Belinda J. Krishek, Stephen J. Moss * and Trevor G. Smart

1. The interaction of Zn²⁺ and H⁺ ions with GABA_A receptors was examined using Xenopus laevis oocytes expressing recombinant GABA_A receptors composed of subunits selected from 1, 1, 2S and types, and by using cultured rat cerebellar granule neurones.

2. The potency of Zn²⁺ as a non-competitive antagonist of GABA-activated responses on 11 receptors was reduced by lowering the external pH from 7·4 to 5·4, increasing the Zn²⁺ IC₅₀ value from 1·2 to 58·3 µM. Zinc-induced inhibition was largely unaffected by alkaline pH up to pH 9·4.

3. For 11 subunits, concentration-response curves for GABA were displaced laterally by Zn²⁺ in accordance with a novel mixed/competitive-type inhibition. The Zn²⁺ IC₅₀ at pH 7·4 was 16·3 µM. Acidification of Ringer solution resulted in a reduced antagonism by Zn²⁺ (IC₅₀, 49·0 µM) without affecting the type of inhibition. At pH 9·4, Zn²⁺ inhibition remained unaffected.

4. The addition of the 2S subunit to the 11 construct caused a marked reduction in the potency of Zn²⁺ (IC₅₀, 615 µM), comparable to that observed with 112S receptors (IC₅₀ 639 µM). GABA concentration-response curves were depressed in a mixed/non-competitive fashion.

5. In cultured cerebellar granule neurones, Zn²⁺ inhibited responses to GABA in a concentration-dependent manner. Lowering external pH from 7·4 to 6·4 increased the IC₅₀ from 139 to 253 µM.

6. The type of inhibition exhibited by Zn²⁺ on cerebellar granule neurones, previously grown in high K⁺-containing culture media, was complex, with the GABA concentration-response curves shifting laterally with reduced slopes and similar maxima. The Zn²⁺-induced shift in the GABA EC₅₀ values was reduced by lowering the external pH from 7·4 to 6·4.

7. The interaction of H⁺ and Zn²⁺ ions on GABA_A receptors suggests that they share either a common regulatory pathway or coincident binding sites on the receptor protein. The apparent competitive mode of block induced by Zn²⁺ on 11 receptors is shared by GABA_A receptors on cerebellar granule neurones, which are known to express -subunit-containing receptors. This novel mechanism is masked when a 2 subunit is incorporated into the receptor complex, revealing further diversity in the response of native GABA_A receptors to endogenous cations.

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