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J. Biol. Chem., Vol. 283, Issue 27, 18538-18544, July 4, 2008

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The Ubiquitin-like Protein Plic-1 Enhances the Membrane Insertion of GABA_A Receptors by Increasing Their Stability within the Endoplasmic Reticulum^*

Richard S. Saliba¹, Menelas Pangalos^¶, and Stephen J. Moss²

From the Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Neuroscience, Pharmacology, and Physiology, University College London, London WC1E 6BT, United Kingdom, and ^¶Wyeth Research, Neuroscience Discovery, Princeton, New Jersey 08852

-Aminobutyric acid receptors (GABA_AR) are the major sites of fast inhibitory neurotransmission in the brain, and a critical determinant for the efficacy of neuronal inhibition is the number of these receptors that are expressed on the neuronal cell surface. GABA_ARs are heteropentamers that can be constructed from seven subunit classes with multiple members; , β, (1–3), , (1–3), , and . Receptor assembly occurs within the endoplasmic reticulum, and it is evident that transport-competent combinations exiting this organelle can access the cell surface, whereas unassembled subunits are ubiquitinated and subject to proteasomal degradation. In a previous report the ubiquitin-like protein Plic-1 was shown to directly interact with GABA_ARs and promote their accumulation at the cell surface. In this study we explore the mechanisms by which Plic-1 regulates the membrane trafficking of GABA_ARs. Using both recombinant and neuronal preparations it was apparent that Plic-1 increased the stability of endoplasmic reticulum resident GABA_ARs together with an increase in the abundance of poly-ubiquitinated receptor subunits. Furthermore, Plic-1 elevated cell surface expression levels by selectively increasing their rates of membrane insertion. Thus, Plic-1 may play a significant role in regulating the strength of synaptic inhibition by increasing the stability of GABA_ARs within the secretory pathway and thereby promoting their insertion into the neuronal plasma membrane.

Received for publication, March 14, 2008 , and in revised form, April 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS046478, NS048045, NS051195, NS056359, and P01NS054900 (to S. J. M.). This work was also supported by the Medical Research Council (to S. J. M.). 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.

¹ Supported by a postdoctoral fellowship from the Epilepsy Foundation.

² To whom correspondence should be addressed. E-mail: sjmoss{at}mail.med.upenn.edu.

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