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J. Biol. Chem., Vol. 277, Issue 32, 29268-29274, August 9, 2002

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

Daniel B. McClatchy, Charlotte R. Knudsen^§, Brian F. Clark^§, Richard A. Kahn^¶, Randy A. Hall, and Allan I. Levey^**

From the  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.

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