Agonist and potentiation actions of n-octanol on gamma-aminobutyric acid type A receptors.
The n-octanol effects on the gamma-aminobutyric acid type A (GABAA) receptor were studied in human embryonic kidney 293 cells transfected with alpha1, beta2, and gamma2S subunit cDNAs. GABA-evoked currents had an EC50 of 13.3 +/- 1.7 microM and a Hill coefficient (nH) of 1.4 +/- 0.1. n-Octanol was also capable of evoking a small current with an EC50 of 1000 microM and an nH of 2. In addition, n-octanol modulated GABA-induced currents in a concentration-dependent manner. Coapplications of n-octanol increased peak currents evoked by 3 microM GABA with an EC50 of 190 microM and an nH of 1.8. The extent of potentiation decreased with increasing GABA concentrations and no potentiation was observed when n-octanol was coapplied with 1000 microM GABA. One-minute preapplication of 1000 microM n-octanol slightly potentiated 3 microM GABA-induced current, whereas it suppressed 300 microM GABA-induced current to 16% of the control, suggesting that 84% of the receptors underwent desensitization. Two models were used to explain n-octanol agonistic and potentiating actions on the alpha1beta2gamma2S GABAA receptor: n-octanol binds to multiple sites to exert multiple actions, or n-octanol acts as a partial agonist to manifest these actions. The partial agonist model is unique because it is a simpler model to explain n-octanol actions on the GABAA receptor.
Kurata
Y
Y
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois, USA.
Marszalec
W
W
Yeh
J Z
JZ
Narahashi
T
T
D020003:1-Octanol / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D058785:GABA-A Receptor Agonists; D006801:Humans; D008954:Models, Biological; D011963:Receptors, GABA-A / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D020003:1-Octanol