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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
31
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pubmed:dateCreated |
2003-7-28
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Cresols,
http://linkedlifedata.com/resource/pubmed/chemical/Heparin,
http://linkedlifedata.com/resource/pubmed/chemical/ITPR1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Inositol 1,4,5-Trisphosphate...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ryanodine Receptor Calcium Release...,
http://linkedlifedata.com/resource/pubmed/chemical/Tacrolimus Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/chlorocresol,
http://linkedlifedata.com/resource/pubmed/chemical/tacrolimus binding protein 1B
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
28856-64
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pubmed:dateRevised |
2007-7-18
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pubmed:meshHeading |
pubmed-meshheading:12754204-Adenosine Triphosphate,
pubmed-meshheading:12754204-Animals,
pubmed-meshheading:12754204-Apoptosis,
pubmed-meshheading:12754204-CHO Cells,
pubmed-meshheading:12754204-Calcium,
pubmed-meshheading:12754204-Calcium Channels,
pubmed-meshheading:12754204-Cell Death,
pubmed-meshheading:12754204-Cell Division,
pubmed-meshheading:12754204-Cresols,
pubmed-meshheading:12754204-Cricetinae,
pubmed-meshheading:12754204-Cytoplasm,
pubmed-meshheading:12754204-Gene Expression,
pubmed-meshheading:12754204-Heparin,
pubmed-meshheading:12754204-Humans,
pubmed-meshheading:12754204-Inositol 1,4,5-Trisphosphate Receptors,
pubmed-meshheading:12754204-Phenotype,
pubmed-meshheading:12754204-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:12754204-Receptors, Purinergic P2,
pubmed-meshheading:12754204-Recombinant Proteins,
pubmed-meshheading:12754204-Ryanodine Receptor Calcium Release Channel,
pubmed-meshheading:12754204-Signal Transduction,
pubmed-meshheading:12754204-Tacrolimus Binding Proteins,
pubmed-meshheading:12754204-Transfection
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pubmed:year |
2003
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pubmed:articleTitle |
Dysregulated ryanodine receptors mediate cellular toxicity: restoration of normal phenotype by FKBP12.6.
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pubmed:affiliation |
Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. georgech@cf.ac.uk
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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