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The Journal of Neuroscience, July 1, 2002, 22(13):5328-5333

Identification of a  Subunit TM2 Residue Mediating Proton Modulation of GABA Type A Receptors

Megan E. Wilkins, Alastair M. Hosie, and Trevor G. Smart

School of Pharmacy, Department of Pharmacology, University of London, London, WC1N 1AX, United Kingdom

GABA type A (GABA_A) receptors are functionally regulated by external protons in a manner dependent on the receptor subunit composition. Although H⁺ can regulate the open probability of single GABA ion channels, exactly what residues and receptor subunits are responsible for proton-induced modulation remain unknown. This study resolves this issue by using recombinant 1i subunit GABA_A receptors expressed in human embryonic kidney cells. The potentiating effect of low external pH on GABA responses exhibited p_Ka in accord with the involvement of histidine and/or cysteine residues. The exposure of GABA_A receptors to the histidine-modifying reagent DEPC ablated regulation by H⁺, implicating the involvement of histidine residues rather than cysteines in proton regulation. Site-specific substitution of all conserved external histidines to alanine on the  subunits revealed that H267 alone, in the TM2 domain, is important for H⁺ regulation. These results are interpreted as a direct protonation of H267 on 1i receptors rather than an involvement in signal transduction. The opposing functional effects induced by Zn²⁺ and H⁺ at this single histidine residue most likely reflect differences in charge delocalization on the imidazole rings in the mouth of the GABA_A receptor ion channel. Additional substitutions of H267 in  subunits with other residues possessing charged side chains (glutamate and lysine) reveal that this area of the ion channel can profoundly influence the functional properties of GABA_A receptors.

Key words: GABA_A receptor; pH modulation; subunit; histidine, H⁺; ion channel

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22135328-06$05.00/0

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