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

  1. Yasutaka Kurata1,
  2. William Marszalec,
  3. Jay Z. Yeh and
  4. Toshio Narahashi
  1. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois

    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

    • 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

    • ↵1 Current affiliation: Department of Physiology, Kamazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa 920-02, Japan.

    • This work was supported by a grant from the National Institutes of Health AA07836.

    • Abbreviations:
      HEK
      human embryonic kidney
      DRG
      dorsal root ganglion
      EC50
      concentration producing 50% maximal response
      IC50
      concentration producing 50% inhibition
      • Received November 2, 1998.
      • Accepted March 8, 1999.
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    1. Molecular Pharmacology June 1, 1999 vol. 55 no. 6 1011-1019
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