Abstract
The n-octanol effects on the γ-aminobutyric acid type A (GABAA) receptor were studied in human embryonic kidney 293 cells transfected with α1, β2, and γ2S subunit cDNAs. GABA-evoked currents had an EC50 of 13.3 ± 1.7 μM 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 μM 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 μM GABA with an EC50 of 190 μM and an nH of 1.8. The extent of potentiation decreased with increasing GABA concentrations and no potentiation was observed whenn-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 α1β2γ2S GABAA receptor: n-octanol binds to multiple sites to exert multiple actions, orn-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.
Footnotes
- Received November 2, 1998.
- Accepted March 8, 1999.
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Send reprint requests to: Dr. Toshio Narahashi Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Ave., Chicago, IL. E-mail: tna597{at}anima.nums.nwu.edu
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↵1 Current affiliation: Department of Physiology, Kamazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa 920-02, Japan.
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This work was supported by a grant from the National Institutes of Health AA07836.
- The American Society for Pharmacology and Experimental Therapeutics
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