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J. Biol. Chem., Vol. 278, Issue 31, 28727-28735, August 1, 2003

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Identification of a Key Determinant of Ryanodine Receptor Type 1 Required for Activation by 4-Chloro-m-cresol^*

James D. Fessenden  , Claudio F. Perez , Sam Goth ¶, Isaac N. Pessah ¶ and Paul D. Allen 

From the Department of Anesthesia Research, Brigham and Women's Hospital, Boston, Massachusetts 02115 and the ^¶Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616

4-Chloro-m-cresol (4-CmC) is a potent and specific activator of the intracellular Ca²⁺ release channel, the ryanodine receptor (RyR). We have previously shown that RyR1 expressed in dyspedic 1B5 myotubes is activated by 4-CmC, whereas RyR3 is not (Fessenden, J. D., Wang, Y., Moore, R. A., Chen, S. R. W., Allen, P. D., and Pessah, I. N. (2000) Biophys. J. 79, 2509–2525). To identify region(s) on RyR1 that are responsible for mediating activation by 4-CmC, we expressed RyR1-RyR3 chimeric proteins in dyspedic 1B5 myotubes and then measured 4-CmC-induced increases in intracellular Ca²⁺. Substitution of the C-terminal third of RyR1 into RyR3 imparted 4-CmC sensitivity to the resulting chimera, thus suggesting that determinants required for activation by 4-CmC are located in this region. We subdivided the C-terminal third of RyR1 into smaller segments and identified two overlapping regions of RyR1 (amino acids 3769–4180 and 4007–4382) that each imparted 4-CmC sensitivity to RyR3. Substitution of the 173 amino acids of RyR1 common to these two chimeras (amino acids 4007–4180) also weakly restored 4-CmC sensitivity in the resulting chimera. To confirm these findings, we created a complementary set of chimeras containing RyR3 substitutions in RyR1. Substitution of the RyR3 C terminus into RyR1 disrupted 4-CmC sensitivity in the resulting chimera. In addition, substitution of the corresponding RyR3 sequence into positions 4007–4180 of RyR1 disrupted 4-CmC sensitivity. Taken together, these results suggest that essential determinants required for activation of RyR1 by 4-CmC reside within a 173-amino acid region between residues 4007 and 4180.

Received for publication, April 11, 2003 , and in revised form, May 16, 2003.

^* 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 Anesthesia Research, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Tel.: 617-732-6881; Fax: 617-732-6927; E-mail: fessenden{at}zeus.bwh.harvard.edu.

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