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J. Biol. Chem., Vol. 283, Issue 10, 6321-6329, March 7, 2008

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Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies^*

From the Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7260

Skeletal muscle excitation-contraction coupling involves activation of homotetrameric ryanodine receptor ion channels (RyR1s), resulting in the rapid release of Ca²⁺ from the sarcoplasmic reticulum. Previous work has shown that Ca²⁺ release is impaired by mutations in RyR1 linked to Central Core Disease and Multiple Minicore Disease. We studied the consequences of these mutations on RyR1 function, following their expression in human embryonic kidney 293 cells and incorporation in lipid bilayers. RyR1-G4898E, -G4898R, and -V4926/I4927 mutants in the C-terminal pore region of RyR1 and N-terminal RyR1-R110W/L486V mutant all showed negligible Ca²⁺ permeation and loss of Ca²⁺-dependent channel activity but maintained reduced K⁺ conductances. Co-expression of wild type and mutant RyR1s resulted in Ca²⁺-dependent channel activities that exhibited intermediate Ca²⁺ selectivities compared with K⁺, which suggested the presence of tetrameric RyR1 complexes composed of wild type and mutant subunits. The number of wild-type subunits to maintain a functional heterotetrameric channel differed among the four RyR1 mutants. The results indicate that homozygous RyR1 mutations associated with core myopathies abolish or greatly reduce sarcoplasmic reticulum Ca²⁺ release during excitation-contraction coupling. They further suggest that in individuals, expressing wild type and mutant alleles, a substantial portion of RyR1 channels is able to release Ca²⁺ from sarcoplasmic reticulum.

Received for publication, August 31, 2007 , and in revised form, November 20, 2007.

^* This work was supported by National Institutes of Health Grant AR018687. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260. Tel.: 919-966-5021; Fax: 919-966-2852; E-mail: meissner{at}med.unc.edu.

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