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J. Biol. Chem., Vol. 279, Issue 22, 22833-22840, May 28, 2004

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A TM2 Residue in the 1 Subunit Determines Spontaneous Opening of Homomeric and Heteromeric -Aminobutyric Acid-gated Ion Channels^*

Angela Miko, Elena Werby, Hui Sun, Julia Healey, and Li Zhang

From the Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-8115

-Aminobutyric acid type A (GABA_A) receptors are major inhibitory neurotransmitter-gated ion channels in the central nervous system. GABA_A receptors consist of multiple subunits and exhibit distinct pharmacological and channel properties. Of all GABA_A receptor subunits, the subunit is thought to be a key component for the functionality of the receptors. Certain types of GABA_A receptors have been found to be constitutively active. However, the molecular basis for spontaneous opening of channels of these receptors is not totally understood. In this study, we showed that channels that contain the 1 but not 3 subunits opened spontaneously when these subunits were expressed homomerically or co-expressed with other types of GABA_A receptor subunits in Xenopus oocytes. Using subunit chimeras and site-directed mutagenesis, we localized a key amino acid residue, a serine at position 265, that is critical in conferring an open state of the 1 subunit-containing GABA_A receptors in the absence of agonist. Moreover, some point mutations of Ser-265 also produced constitutively active channels. The magnitude of spontaneous activity of these receptors was correlated with the molecular volume of the residue at 265 for both homomeric and heteromeric GABA_A receptors, suggesting that the spontaneous activity of the 1 subunit-containing GABA_A receptors may be mediated through a similar molecular mechanism that is dependent on the molecular volume of the residue at 265.

Received for publication, March 8, 2004

^* 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 should be addressed: Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Park Bldg., Rm. 150, Bethesda, MD 20892-8115. Tel.: 301-443-1236; Fax: 301-480-6882; E-mail: lzhang{at}niaaa.nih.gov.

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