JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

A more recent version of this article appeared on August 1, 2003
This Article
Right arrow Full Text (Accepted Manuscript)
Right arrow All Versions of this Article:
278/31/28856    most recent
M212440200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by George, C. H.
Right arrow Articles by Lai, F. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by George, C. H.
Right arrow Articles by Lai, F. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Papers In Press, published online ahead of print May 16, 2003
J. Biol. Chem, 10.1074/jbc.M212440200
Submitted on December 6, 2002
Revised on April 29, 2003
Accepted on May 16, 2003

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

Department of Cardiology, Wales Heart Research Institute, Cardiff, Wales CF14 4XN

Corresponding Author: georgech{at}cf.ac.uk

Ca2+ homeostasis is a vital 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 (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 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 cell death mediated specifically 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+ signalling and highlight a key modulatory role of FKBP12.6 in hRyR2 Ca2+ channel function.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
C. H. George
Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance?
Cardiovasc Res, January 15, 2008; 77(2): 302 - 314.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
C. H. George, S. A. Rogers, B. M.A. Bertrand, R. E.A. Tunwell, N. L. Thomas, D. S. Steele, E. V. Cox, C. Pepper, C. J. Hazeel, W. C. Claycomb, et al.
Alternative Splicing of Ryanodine Receptors Modulates Cardiomyocyte Ca2+ Signaling and Susceptibility to Apoptosis
Circ. Res., March 30, 2007; 100(6): 874 - 883.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
B. L. Williams and W. I. Lipkin
Endoplasmic reticulum stress and neurodegeneration in rats neonatally infected with borna disease virus.
J. Virol., September 1, 2006; 80(17): 8613 - 8626.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
C. H. George, H. Jundi, N. Walters, N. L. Thomas, R. R. West, and F. A. Lai
Arrhythmogenic Mutation-Linked Defects in Ryanodine Receptor Autoregulation Reveal a Novel Mechanism of Ca2+ Release Channel Dysfunction
Circ. Res., January 6, 2006; 98(1): 88 - 97.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
N. Lowri Thomas, C. H. George, and F. Anthony Lai
Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death
Cardiovasc Res, October 1, 2004; 64(1): 52 - 60.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
C. H. George, H. Jundi, N. L. Thomas, M. Scoote, N. Walters, A. J. Williams, and F. A. Lai
Ryanodine Receptor Regulation by Intramolecular Interaction between Cytoplasmic and Transmembrane Domains
Mol. Biol. Cell, June 1, 2004; 15(6): 2627 - 2638.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
C. H. George, G. V. Higgs, and F. A. Lai
Ryanodine Receptor Mutations Associated With Stress-Induced Ventricular Tachycardia Mediate Increased Calcium Release in Stimulated Cardiomyocytes
Circ. Res., September 19, 2003; 93(6): 531 - 540.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.