Protons inhibit Cl- conductance by direct or allosteric interaction with the GABA-binding site in the rat recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptor.
Functional roles of external pH on the Cl- conductance were examined on Xenopus oocytes expressing rat recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors. Acidic pH inhibited GABA-response in a reversible and concentration-dependent manner, significantly increasing the EC50 without appreciably changing the slope or maximal currents induced by GABA in the alpha1beta2gamma2L and alpha1beta2 receptors. In contrast, protonation did not influence the pentobarbital-gated currents in the alpha1beta2gamma2L receptors, suggesting that protons do not modulate channel activity by directly affecting the channel gating process. Protons competitively inhibited the bicuculline-induced antagonism on GABA in the alpha1beta2gamma2L receptors. The data support the hypothesis that protons inhibit GABAA receptor function by direct or allosteric interaction with the GABA-binding site.
Wang
Ming-De
MD
Umeå Neurosteroid Research Center, Department of Clinical Science, Obstetrics and Gynecology, Umeå University, Bldg 5B, 5th floor, S-901 85 Umeå, Sweden. mingde.wang@obgyn.umu.se
Rahman
Mozibur
M
Zhu
Di
D
D000494:Allosteric Regulation; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002712:Chlorides / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes; D010634:Phenobarbital / Q000494:pharmacology; D011522:Protons; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002712:Chlorides; D018756:GABA Antagonists; D018757:GABA Modulators; C546242:Gabra1 protein, rat; C502185:Gabrb2 protein, rat; D011522:Protons; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline; D010634:Phenobarbital