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Dysregulated ryanodine receptors mediate cellular toxicity: restoration of normal phenotype by FKBP12.6

George, Christopher, Higgs, Gemma, Mackrill, John J. and Lai, Francis Anthony 2003. Dysregulated ryanodine receptors mediate cellular toxicity: restoration of normal phenotype by FKBP12.6. Journal of biological chemistry 278 (31) , pp. 28856-28864. 10.1074/jbc.M212440200

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Abstract

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, CHOhRyR2) had similar resting cytoplasmic Ca2+ levels ([Ca2+]c) to wild-type CHO cells (CHOWT) 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
ISSN: 1083-351X
Last Modified: 27 Mar 2020 02:37
URI: http://orca-mwe.cf.ac.uk/id/eprint/31

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