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J. Biol. Chem., Vol. 277, Issue 47, 44722-44730, November 22, 2002
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From the 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.
Homer Regulates Gain of Ryanodine Receptor Type 1 Channel
Complex*
,
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
*
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:
inpessah@ucdavis.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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