Structure of α6β3δ GABAA receptors and their lack of ethanol sensitivity

Authors


Address correspondence and reprint requests to Erwin Sigel, Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012, Switzerland. E-mail: erwin.sigel@mci.unibe.ch

Abstract

Delta (δ) subunit containing GABAA receptors are expressed extra-synaptically and mediate tonic inhibition. In cerebellar granule cells, they often form a receptor together with α6 subunits. We were interested to determine the architecture of these receptors. We predefined the subunit arrangement of 24 different GABAA receptor pentamers by subunit concatenation. These receptors (composed of α6, β3 and δ subunits) were expressed in Xenopus oocytes and their electrophysiological properties analyzed. Currents elicited in response to GABA were determined in presence and absence of 3α, 21-dihydroxy-5α-pregnan-20-one and to 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. α636/δ receptors showed a substantial response to GABA alone. Three receptors, β36-δ/α63, α6363-δ and β3-δ-β363, were only uncovered in the combined presence of the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one with GABA. All four receptors were activated by 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. None of the functional receptors was modulated by physiological concentrations (up to 30 mM) of ethanol. GABA concentration response curves indicated that the δ subunit can contribute to the formation of an agonist site. We conclude from the investigated receptors that the δ subunit can assume multiple positions in a receptor pentamer composed of α6, β3 and δ subunits.

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