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  • Title: Molecular basis for modulation of recombinant alpha1beta2gamma2 GABAA receptors by protons.
    Author: Huang RQ, Chen Z, Dillon GH.
    Journal: J Neurophysiol; 2004 Aug; 92(2):883-94. PubMed ID: 15028749.
    Abstract:
    We have previously shown that extracellular protons inhibit recombinant and native GABA(A) receptors. In this report, we studied the site(s) and mechanism by which protons modulate the GABA(A) receptor. Whole cell GABA-activated currents were recorded from human embryonic kidney (HEK) 293 cells expressing recombinant alpha1beta2gamma2 GABA(A) receptors. Protons competitively inhibited the response to GABA and bicuculline. In contrast, change in pH did not influence direct gating of the channel by pentobarbital, and it did not influence spontaneous channel openings in alpha1(L264T)beta2gamma2 receptors, suggesting pH does not modulate channel activity by affecting the channel gating process directly. To test the hypothesis that protons modulate GABA(A) receptors at the ligand binding site, we systemically mutated N-terminal residues known to be involved in GABA binding and assessed effects of pH on these mutant receptors. Site-specific mutation of beta2 Y205 to F or alpha1 F64 to A, both of which are known to influence GABA binding, significantly reduced pH sensitivity of the GABA response. These mutations did not affect Zn(2+) sensitivity, suggesting that H(+) and Zn(2+) do not share a common site of action. Additional experiments further tested this possibility. Treatment with the histidine-modifying reagent diethylpyrocarbonate (DEPC) reduced Zn(2+)-mediated inhibition of GABA(A) receptors but had no effect on proton-induced inhibition of GABA currents. In addition, mutation of residues known to be involved in Zn(2+) modulation had no effect on pH modulation of GABA(A) receptors. Our results support the hypothesis that protons inhibit GABA(A) receptor function by direct or allosteric interaction with the GABA binding site. In addition, the sites of action of H(+) and Zn(2+) in GABA(A) receptors are distinct.
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