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J. Biol. Chem. 277 (32): 29268-29274

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2*

Daniel B. McClatchyDagger , Charlotte R. Knudsen§, Brian F. Clark§, Richard A. Kahn, Randy A. Hall||, and Allan I. LeveyDagger **

From the Dagger  Center for Neurodegenerative Diseases, Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, the § Institute of Molecular and Structural Biology, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark, the  Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, and the || Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322

The activation of the muscarinic acetylcholine receptor (mAChR) family, consisting of five subtypes (M1-M5), produces a variety of physiological effects throughout the central nervous system. However, the role of each individual subtype remains poorly understood. To further elucidate signal transduction pathways for specific subtypes, we used the most divergent portion of the subtypes, the intracellular third (i3) loop, as bait to identify interacting proteins. Using a brain pull-down assay, we identify elongation factor 1A2 (eEF1A2) as a specific binding partner to the i3 loop of M4, and not to M1 or M2. In addition, we demonstrate a direct interaction between these proteins. In the rat striatum, the M4 mAChR colocalizes with eEF1A2 in the soma and neuropil. In PC12 cells, endogenous eEF1A2 co-immunoprecipitates with the endogenous M4 mAChR, but not with the endogenous M1 mAChR. In our in vitro model, M4 dramatically accelerates nucleotide exchange of eEF1A2, a GTP-binding protein. This indicates the M4 mAChR is a guanine exchange factor for eEF1A2. eEF1A2 is an essential GTP-binding protein for protein synthesis. Thus, our data suggest a novel role for M4 in the regulation of protein synthesis through its interaction with eEF1A2.

* This work was supported by National Research Service Award Predoctoral Grant NS43094-01 and National Institutes of Health Grant NS30454.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.

** To whom correspondence should be addressed: Center for Neurodegenerative Diseases, Dept. of Neurology, Emory University School of Medicine, Whitehead Biomedical Research Bldg., Rm. 505, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-5006; Fax: 404-727-3999; E-mail: alevey@emory.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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