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J. Biol. Chem., Vol. 282, Issue 43, 31113-31123, October 26, 2007

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Endoplasmic Reticulum Chaperones Stabilize Nicotinic Receptor Subunits and Regulate Receptor Assembly^*

From the Department of Neurobiology and Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637

We examined interactions between the endoplasmic reticulum (ER) chaperones calnexin (CN), ERp57, and immunological heavy chain-binding protein (BiP) and nicotinic acetylcholine receptor (nAChR) subunits. The three chaperones rapidly associate with newly synthesized nAChR subunits. Interactions between nAChR subunits and ERp57 occur via transient intermolecular disulfide bonds and do not require subunit N-linked glycosylation. The associations of ERp57 or CN with AChR subunits are long lived and prolong subunit lifetime 10-fold. Coexpression of CN or ERp57 alone does not affect nAChR assembly or trafficking, but together they cause a significant decrease in nAChR expression and assembly. In contrast, associations with BiP are shorter lived and do not alter nAChR expression and assembly. However, a mutated BiP that slows its dissociation significantly increases its associations and decreases nAChR expression and assembly. Our results suggest that interactions with the chaperones regulate the levels of nAChRs assembled in the ER by stabilizing and sequestering subunits during assembly.

Received for publication, June 29, 2007 , and in revised form, August 17, 2007.

^* This work was supported in part by a National Institutes of Health training grant (to C. P. W.) and by grants from NIDA and NINDS, National Institutes of Health, and the Alzheimer's Association (to W. N. G.). 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, University of Chicago, 947 E. 58th St., Chicago, IL 60637. Tel.: 773-702-1763; Fax: 773-702-3774; E-mail: wgreen{at}uchicago.edu.

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