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J. Biol. Chem., Vol. 278, Issue 31, 28856-28864, August 1, 2003

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Dysregulated Ryanodine Receptors Mediate Cellular Toxicity

RESTORATION OF NORMAL PHENOTYPE BY FKBP12.6^*

Christopher H. George  , Gemma V. Higgs , John J. Mackrill ¶ and F. Anthony Lai 

From the Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom and the ^¶Department of Biochemistry, University College Cork, Cork, Ireland

Ca²⁺ homeostasis is a vital cellular control mechanism in which Ca²⁺ release from intracellular stores plays a central role. Ryanodine receptor (RyR)-mediated Ca²⁺ release is a key modulator of Ca²⁺ homeostasis, and the defective regulation of RyR is pathogenic. However, the molecular events underlying RyR-mediated pathology remain undefined. Cells stably expressing recombinant human RyR2 (Chinese hamster ovary cells, CHO^hRyR2) had similar resting cytoplasmic Ca²⁺ levels ([Ca²⁺]_c) to wild-type CHO cells (CHO^WT) but exhibited increased cytoplasmic Ca²⁺ flux associated with decreased cell viability and proliferation. Intracellular Ca²⁺ flux increased with human RyR2 (hRyR2) expression levels and determined the extent of phenotypic modulation. Co-expression of FKBP12.6, but not FKBP12, or incubation of cells with ryanodine suppressed intracellular Ca²⁺ flux and restored normal cell viability and proliferation. Restoration of normal phenotype was independent of the status of resting [Ca²⁺]_c or ER Ca²⁺ load. Heparin inhibition of endogenous inositol trisphosphate receptors (IP₃R) had little effect on intracellular Ca²⁺ handling or viability. However, purinergic stimulation of endogenous IP₃R resulted in apoptotic cell death mediated by hRyR2 suggesting functional interaction occurred between IP₃R and hRyR2 Ca²⁺ release channels. These data demonstrate that defective regulation of RyR causes altered cellular phenotype via profound perturbations in intracellular Ca²⁺ signaling and highlight a key modulatory role of FKBP12.6 in hRyR2 Ca²⁺ channel function.

Received for publication, December 6, 2002 , and in revised form, April 29, 2003.

^* This work was supported by British Heart Foundation Research Fellowship FS2000020 (to C. H. G.) and by British Heart Foundation Grant PG99087 (to F. A. L.). 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. Tel.: 44-292-074-4431; Fax: 44-292-074-3500; E-mail: georgech{at}cf.ac.uk.

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