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J. Biol. Chem., Vol. 280, Issue 40, 34088-34095, October 7, 2005

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Ubiquilin-1 Regulates Nicotine-induced Up-regulation of Neuronal Nicotinic Acetylcholine Receptors^*

Mary Beth Ficklin, Shengli Zhao, and Guoping Feng1

From the Departments of Neurobiology and Pathology, Duke University Medical Center, Durham, North Carolina 27710

Chronic exposure to nicotine, as in tobacco smoking, up-regulates nicotinic acetylcholine receptor surface expression in neurons. This up-regulation has been proposed to play a role in nicotine addiction and withdrawal. The regulatory mechanisms behind nicotine-induced up-regulation of surface nicotinic acetylcholine receptors remain to be determined. It has recently been suggested that nicotine stimulation acts through increased assembly and maturation of receptor subunits into functional pentameric receptors. Studies of muscle nicotinic acetylcholine receptors suggest that the availability of unassembled subunits in the endoplasmic reticulum can be regulated by the ubiquitin-proteosome pathway, resulting in altered surface expression. Here, we describe a role for ubiquilin-1, a ubiquitin-like protein with the capacity to interact with both the proteosome and ubiquitin ligases, in regulating nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors. Ubiquilin-1 interacts with unassembled 3 and 4 subunits when coexpressed in heterologous cells and interacts with endogenous nicotinic acetylcholine receptors in neurons. Coexpression of ubiquilin-1 and neuronal nicotinic acetylcholine receptors in heterologous cells dramatically reduces the expression of the receptors on the cell surface. In cultured superior cervical ganglion neurons, expression of ubiquilin-1 abolishes nicotine-induced up-regulation of nicotinic acetylcholine receptors but has no effect on the basal level of surface receptors. Coimmunostaining shows that the interaction of ubiquilin-1 with the 3 subunit draws the receptor subunit and proteosome into a complex. These data suggest that ubiquilin-1 limits the availability of unassembled nicotinic acetylcholine receptor subunits in neurons by drawing them to the proteosome, thus regulating nicotine-induced up-regulation.

Received for publication, June 22, 2005 , and in revised form, July 19, 2005.

^* This work was supported in part by the Duke University Medical Center Medical Scientist Training Program (to M. B. F.) and a postdoctoral fellowship from the Ruth K. Broad Biomedical Research Foundation, Inc. (to S. Z.). This work was also supported by the Alfred P. Sloan Research Fellowship, the Klingenstein Fellowship in the Neurosciences, the EJLB Foundation's Scholar Research Program, Scientist Development Grant 0230064N from the American Heart Association, and National Institute of Health Grant NS042609 (to G. 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.

¹ To whom correspondence should be addressed: Dept. of Neurobiology, Box 3209, Duke University Medical Center, Research Drive, Durham, NC 27710. Tel.: 919-668-1657; Fax: 919-668-1891; E-mail: feng{at}neuro.duke.edu.

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