Vol. 55, Issue 6, 1011-1019, June 1999

Agonist and Potentiation Actions of n-Octanol on -Aminobutyric Acid Type A Receptors

Yasutaka Kurata,¹ William Marszalec, Jay Z. Yeh, and Toshio Narahashi

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois

The n-octanol effects on the -aminobutyric acid type A (GABA_A) receptor were studied in human embryonic kidney 293 cells transfected with 1, 2, and 2S subunit cDNAs. GABA-evoked currents had an EC₅₀ of 13.3 ± 1.7 µM and a Hill coefficient (n_H) of 1.4 ± 0.1. n-Octanol was also capable of evoking a small current with an EC₅₀ of 1000 µM and an n_H 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 µM GABA with an EC₅₀ of 190 µM and an n_H of 1.8. The extent of potentiation decreased with increasing GABA concentrations and no potentiation was observed when n-octanol was coapplied with 1000 µM GABA. One-minute preapplication of 1000 µM n-octanol slightly potentiated 3 µM GABA-induced current, whereas it suppressed 300 µM 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 122S GABA_A 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 GABA_A receptor.