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J. Biol. Chem., Vol. 279, Issue 20, 20982-20992, May 14, 2004

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Gating Allosterism at a Single Class of Etomidate Sites on _122L GABA_A Receptors Accounts for Both Direct Activation and Agonist Modulation^*

Dirk Rüsch, Huijun Zhong, and Stuart A. Forman¶||

From the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts 02114, the ^¶Department of Anesthesia, Harvard Medical School, Boston, Massachusetts 02115, and the Department of Anesthesia and Critical Care, University Hospital Schleswig-Holstein, 24105 Kiel, Germany

At clinical concentrations, the potent intravenous general anesthetic etomidate enhances -aminobutyric acid, type A (GABA_A) receptor activity elicited with low -aminobutyric acid (GABA) concentrations, whereas much higher etomidate concentrations activate receptors in the absence of GABA. Therefore, GABA_A receptors may possess two types of etomidate sites: high affinity GABA-modulating sites and low affinity channel-activating sites. However, GABA modulation and direct activation share stereoselectivity for the (R)(+)-etomidate isomer and display parallel dependence on GABA_A subunit isoforms, suggesting that these two actions may be mediated by a single class of etomidate site(s) that exert one or more molecular effects. In this study, we assessed GABA modulation by etomidate using leftward shifts of electrophysiological GABA concentration responses in cells expressing human _122L receptors. Etomidate at up to 100 µM reduced GABA EC₅₀ values by over 100-fold but without apparent saturation, indicating the absence of high affinity etomidate sites. In experiments using a partial agonist, P4S, etomidate both reduced EC₅₀ and increased maximal efficacy, demonstrating that etomidate shifts the GABA_A receptor gating equilibrium toward open states. Results were quantitatively analyzed using equilibrium receptor gating models, wherein a postulated class of equivalent etomidate sites both directly activates receptors and enhances agonist gating. A Monod-Wyman-Changeux co-agonist mechanism with two equivalent etomidate sites that allosterically enhance GABA_A receptor gating independently of agonist binding most simply accounts for direct activation and agonist modulation. This model also correctly predicts the actions of etomidate on GABA_A receptors containing a point mutation that increases constitutive gating activity.

Received for publication, January 15, 2004 , and in revised form, March 11, 2004.

^* This work was supported by National Institutes of Health Grants P01GM58448 and R01GM66724 (to S. A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence and reprint requests should be addressed: Dept. of Anesthesia and Critical Care, CLN-3, Massachusetts General Hospital, Boston, MA 02114. Tel.: 617-724-5156; Fax: 617-724-8644; E-mail: saforman{at}partners.org.

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