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Modulation of GABA A Receptor Function by Alcohols: Effects of Subunit Composition and Differential Effects of Ethanol
Author(s) -
Whitten R. J.,
Maitra R.,
Reynolds J. N.
Publication year - 1996
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1996.tb01128.x
Subject(s) - gabaa receptor , inverse agonist , gabaa rho receptor , chemistry , receptor , agonist , gamma aminobutyric acid , gamma subunit , partial agonist , pharmacology , biophysics , endocrinology , biochemistry , medicine , protein subunit , biology , gene
We sought to test the hypotheses that closely related alcohols would have effects on GABA A receptor function that were not predicted by differences in lipid solubility, and that the subunit structure of the GABA A receptor would significantly affect the actions of different alcohols. Cloned subunits of human GABA A receptors were expressed in Xenopus oocytes, and two‐electrode voltage‐clamp recording was used to quantify the membrane current response to GABA A in the presence and absence of different alcohols. 1‐Butanol and 2‐butanol differentially potentiated the response to 20 μM GABA in oocytes expressing the α 1 β 2 γ 2L and α 2 β 2 γ 2L , receptor isoforms. In the α 1 β 2 γ 2L receptor construct, 1‐butanol was more potent than 2‐butanol to potentiate GABA, receptor function, but 2‐butanol had a greater efficacy. In the α 2 β 2 receptor construct, 1‐butanol and 2‐butanol were equipotent, but 2‐butanol again had a greater efficacy. In the a2p2 receptor construct, both 1‐butanol and 2‐butanol produced large potentiations of the current response to 3 μM GABA. The efficacy for butanol potentiation of GABA responses in the absence of a γ 2L subunit was greater, but the potency was greatly reduced. Low concentrations (20 mM) of ethanol potentiated GABA responses in the α 1 β 2 γ 2L receptor construct. Ethanol potentiation of GABA A receptor function was completely blocked by the benrodiazepine receptor partial inverse agonist R015‐4513 at a concentration (0.5 μM) that did not alter the control GABA response. In contrast, R015‐4513 did not block potentiation of GABA A receptor activity induced by npropanol, 1‐butanol, 2‐butanol, 1‐heptanol, or propofol (2,0‐diisopropylphenol). These results suggest that alcohols have specific interactions with GABA A receptors, and that ethanol may have unique effects not shared by other longer chain alcohols.