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J. Biol. Chem., Vol. 283, Issue 38, 26128-26136, September 19, 2008

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Multiple Modes for Conferring Surface Expression of Homomeric β1 GABA_A Receptors^*

From the Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110

The -aminobutyric acid type A (GABA_A) receptor assembles from individual subunits to form ligand-gated ion channels. Human (h) β3 subunits assemble to form homomeric surface receptors in somatic cells, but hβ1 subunits do not. We have identified three distinct sets of amino acid residues in the N-terminal extracellular domain of the hβ1 subunit, which when mutated to the homologous residue in hβ3 allow expression as a functional homomeric receptor. The three sets likely result in three modes of assembly. Mode 1 expression results from a single amino acid change at residue hβ1 Asp-37. Mode 2 expression results from mutations of residues between positions 44 and 73 together with residues between positions 169 and 173. Finally, mode 3 results from the mutations A45V and K196R. Examination of homology-based structural models indicates that many of the residues are unlikely to be involved in physical inter-subunit interactions, suggesting that a major alteration is stabilization of an assembly competent form of the subunit. These mutations do not, however, have a major effect on the surface expression of heteromeric receptors which include the 1 subunit.

Received for publication, February 19, 2008 , and in revised form, July 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P01 GM47969 and NS22356. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table and Figs. 1–3.

² The Russell and Mary Shelden Professor of Anesthesiology.

¹ To whom correspondence should be addressed: Dept. of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8054, St. Louis, MO 63110. Tel.: 314-362-8565; Fax: 314-362-8571; E-mail: john{at}morpheus.wustl.edu.

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