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J. Biol. Chem. 277 (47): 44722-44730

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

Homer Regulates Gain of Ryanodine Receptor Type 1 Channel Complex*

Wei FengDagger , Jiancheng Tu§, Tianzhong Yang, Patty Shih Vernon§, Paul D. Allen, Paul F. Worley§, and Isaac N. PessahDagger ||

From the Dagger  Department of Molecular Biosciences, University of California, Davis, California 95616, the § Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the  Department of Anesthesia, Preoperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115

Homer proteins form an adapter system that regulates coupling of group 1 metabotropic glutamate receptors with intracellular inositol trisphosphate receptors and is modified by neuronal activity. Here, we demonstrate that Homer proteins also physically associate with ryanodine receptors type 1 (RyR1) and regulate gating responses to Ca2+, depolarization, and caffeine. In contrast to the prevailing notion of Homer function, Homer1c (long form) and Homer1-EVH1 (short form) evoke similar changes in RyR activity. The EVH1 domain mediates these actions of Homer and is selectively blocked by a peptide that mimics the Homer ligand. 1B5 dyspedic myotubes expressing RyR1 with a point mutation of a putative Homer-binding domain exhibit significantly reduced (~33%) amplitude in their responses to K+ depolarization compared with cells expressing wild type protein. These results reveal that in addition to its known role as an adapter protein, Homer is a direct modulator of Ca2+ release gain. Homer is the first example of an "adapter" that also modifies signaling properties of its target protein. The present work reveals a novel mechanism by which Homer directly modulates the function of its target protein RyR1 and excitation-contraction coupling in skeletal myotubes. This form of regulation may be important in other cell types that express Homer and RyR1.

* This work was supported by National Institutes of Health Grants AR17605 (to P. D. A. and I. N. P.), ES10173 and ES11269 (to I. N. P.), and DA10309 and MH01153 (to P. F. W.).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: Dept. of Molecular Biosciences, School of Veterinary Medicine, One Shields Ave., University of California, Davis, CA 95616. E-mail:

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

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