Selective effects of alcohols on gamma-aminobutyric acid A receptor subunits expressed in human embryonic kidney cells.
Several previous studies implicated alpha 6 and gamma 2L subunits as potential determinants of gamma-aminobutyric acid A (GABAA) receptor channel sensitivity to alcohol modulation. The effects of ethanol and n-octanol were studied on GABA-induced currents in human embryonic kidney cells transfected to express one of three different GABAA receptor channel subunit combinations: alpha 1 beta 2 gamma 2S, alpha 6 beta 2 gamma 2S or alpha 6 beta 2 gamma 2L. No increase in the current amplitude of any subunit combination was observed after the coapplication of GABA and physiological concentrations (10-100 mM) of ethanol. By contrast, the coapplication of GABA and 100 microM octanol increased the current amplitude by 50% to 100% in all three subunit combinations. Octanol produced a shift of the current dose-response curve toward lower concentrations of GABA. Ethanol was effective in increasing the rate of desensitization produced by higher concentrations of GABA in the alpha 6 beta 2 gamma 2S cells but not the alpha 1 beta 2 gamma 2S combination. This ethanol-induced modification of desensitization was not altered by the presence of the protein kinase inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). These experiments indicate that the presence of alpha 6 or gamma 2L subunits, in itself, does not result in the potentiation of GABA-induced currents by ethanol, as described in some reports. However, the presence of either the alpha 6 or alpha 1 subunit may determine whether the desensitization rate of the GABAA current is affected by the alcohol.
Marszalec
W
W
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois.
Kurata
Y
Y
Hamilton
B J
BJ
Carter
D B
DB
Narahashi
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020003:1-Octanol; D001483:Base Sequence; D002460:Cell Line; D003864:Depression, Chemical; D004622:Embryo, Mammalian / Q000166:cytology; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000196:embryology / Q000648:ultrastructure*; D007700:Kinetics; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D000442:Octanols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics; D012680:Sensitivity and Specificity; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology
D007473:Ion Channels; D007546:Isoquinolines; D046911:Macromolecular Substances; D000442:Octanols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011963:Receptors, GABA-A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020003:1-Octanol