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J. Biol. Chem., Vol. 280, Issue 12, 11713-11722, March 25, 2005

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A Calmodulin Binding Domain of RyR Increases Activation of Spontaneous Ca²⁺ Sparks in Frog Skeletal Muscle^*

George G. Rodney, Gerald M. Wilson, and Martin F. Schneider¶

From the Department of Biochemistry and Molecular Biology and Center for Fluorescence Spectroscopy, University of Maryland School of Medicine, Baltimore, Maryland 21201

The calmodulin C lobe binding region (residues 3614–3643) on the sarcoplasmic reticulum Ca²⁺ release channel (RyR1) is thought to be a region of contact between subunits within RyR1 homotetramer Ca²⁺ release channels. To determine whether the 3614–3643 region is a regulatory site/interaction domain within RyR in muscle fibers, we have investigated the effect of a synthetic peptide corresponding to this region (R3614–3643) on Ca²⁺ sparks in frog skeletal muscle fibers. R3614–3643 (0.2–3.0 µM) promoted the occurrence of Ca²⁺ sparks in a highly cooperative dose-dependent manner, with a half-maximal activation at 0.47 µM and a maximal increase in frequency of 5-fold. A peptide with a single amino acid substitution within R3614–3643 (L3624D) retained the ability to bind Ca²⁺-free calmodulin but did not increase Ca²⁺ spark frequency, suggesting that R3614–3643 does not modulate Ca²⁺ sparks by removal of endogenous calmodulin. Our data support a model in which the calmodulin binding domain of RyR1 modulates channel activity by at least two mechanisms: direct binding of calmodulin as well as interactions with other regions of RyR.

Received for publication, July 20, 2004 , and in revised form, January 6, 2005.

^* This work was supported by an Individual National Research Service Award and by National Institutes of Health (NIH) Grants F32-NS44636 (to G. G. R.) and R01-NS23346 and T32-AR07592 (to M. F. S.). Additional support for the Center of Fluorescence Spectroscopy was provided by NIH Grant P41-RR08119. 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.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201. Tel.: 410-706-7812; Fax: 410-706-8297; E-mail: mschneid{at}umaryland.edu.

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