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 (GABA(A)) recep tor were studied in human embryonic kidney 293 cells transfected with alpha 1, beta 2, and gamma 2S subunit cDNAs. GABA-evoked currents had an EC50 of 13.3 +/- 1.7 mu M and a Hill coefficient (n(H))of 1.4 +/- 0.1. n-Octanol w as also capable of evoking a small current with an EC50 of 1000 mu M and an n(H) of 2. In addition, n-octanol modulated GABA-induced currents in a con centration-dependent manner. Coapplications of n-octanol increased peak cur rents evoked by 3 mu M GABA with an EC50 of 190 mu M and an n(H) of 1.8. Th e extent of potentiation decreased with increasing GABA concentrations and no potentiation was observed when n-octanol was coapplied with 1000 mu M GA BA. One-minute preapplication of 1000 mu M n-octanol slightly potentiated 3 mu M GABA-induced current, whereas it suppressed 300 mu M GABA-induced cur rent to 16% of the control, suggesting that 84% of the receptors underwent desensitization. Two models were used to explain n-octanol agonistic and po tentiating actions on the alpha 1 beta 2 gamma 2S GABA(A) receptor: n-octan ol 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 u nique because it is a simpler model to explain n-octanol actions on the GAB A, receptor.