Evidence for inhibitory effect of the agonist gaboxadol at human alpha 1 beta 2 gamma 2S GABAA receptors.
Gaboxadol (THIP; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is an agonist at GABA(A) receptors. THIP concentrations (0.01-50 mM) were applied rapidly to Sf9 cells expressing the human alpha(1)beta(2)gamma(2S) GABA(A) receptors. The EC(50) values for the peak current in THIP alone or THIP plus 1 microM diazepam were 154 and 53 microM, respectively. In supersaturating THIP (10-50 mM) the rate of current decay increased and an off-current developed when THIP was rapidly removed. The mean currents measured over the first 4 s in 10 mM and higher THIP concentrations were 0.6 or less of the 1 mM THIP mean current. Diazepam (1 microM) increased the 4 s mean current when evoked by 10 to 20 mM THIP but not 50 mM THIP. No similar effects on the current time-course were recorded in supersaturating gamma-aminobutyric acid (GABA) concentrations (50 and 80 mM). The results demonstrate an inhibitory as well as agonist effect of THIP at alpha(1)beta(2)gamma(2S) GABA(A) receptors.
Smith
Morten
M
Molecular and Cellular Physiology, Department of Physiological Sciences, Lund University, Tornavagen 10 BMC F11, 22184 Lund, Sweden.
Lindquist
Catarina E L
CE
Birnir
Bryndis
B
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C546240:GABRA1 protein, human; C546279:GABRG2 protein, human; D007555:Isoxazoles; D021122:Protein Subunits; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol