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Originally published In Press as doi:10.1074/jbc.M100691200 on February 15, 2001

J. Biol. Chem., Vol. 276, Issue 21, 18384-18391, May 25, 2001
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Adjacent Basic Amino Acid Residues Recognized by the COP I Complex and Ubiquitination Govern Endoplasmic Reticulum to Cell Surface Trafficking of the Nicotinic Acetylcholine Receptor alpha -Subunit*

Steven H. KellerDagger §, Jon Lindstrom, Mark Ellisman||, and Palmer TaylorDagger

From the Dagger  Department of Pharmacology, University of California, San Diego, La Jolla, Califronia 92093,  Departments of Neurosciences and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6074, and || Department of Neurosciences, University of California, San Diego, La Jolla, California 92093

The nicotinic acetylcholine receptor in muscle is a ligand-gated ion channel with an ordered subunit arrangement of alpha -gamma -alpha -delta -beta . The subunits are sequestered in the endoplasmic reticulum (ER) and assembled into the pentameric arrangement prior to their exit to the cell surface. Mutating the Arg313-Lys314 sequence in the large cytoplasmic loop of the alpha -subunit to K314Q promotes the trafficking of the mutant unassembled alpha -subunit from the ER to the Golgi in transfected HEK cells, identifying an important determinant that modulates the ER to Golgi trafficking of the subunit. The association of the K314Q alpha -subunit with gamma -COP, a component of COP I coats implicated in Golgi to ER anterograde transport, is diminished to a level comparable to that observed for wild-type alpha -subunits when co-expressed with the beta -, delta -, and gamma -subunits. This suggests that the Arg313-Lys314 sequence is masked when the subunits assemble, thereby enabling ER to Golgi trafficking of the alpha -subunit. Although unassembled K314Q alpha -subunits accumulate in the Golgi, they are not detected at the cell surface, suggesting that a second post-Golgi level of capture exists. Expressing the K314Q alpha -subunit in the absence of the other subunits in ubiquitinating deficient cells (ts20) results in detecting this subunit at the cell surface, indicating that ubiquitination functions as a post-Golgi modulator of trafficking. Taken together, our findings support the hypothesis that subunit assembly sterically occludes the trafficking signals and ubiquitination at specific sites. Following the masking of these signals, the assembled ion channel expresses at the cell surface.

* This work was supported by an American Heart Association Fellowship and a grant from the Cystic Fibrosis Foundation (to S. K.), National Institutes of Health Grant NS11323, a grant from the Smokeless Tobacco Research Council, Inc. (to J. L.), and National Institutes of Health Grant GM18360 (to P. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Dept. of Medicine 0693, University of California, San Diego, La Jolla, CA 92093.

To whom correspondence should be addressed. Tel.: 858-822-3386; E-mail: shkeller@ucsd.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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