%0 Journal Article %1 Kuba_2005_14104 %A Kubalova, Zuzana %A Terentyev, Dmitry %A Viatchenko-Karpinski, Serge %A Nishijima, Yoshinori %A Gy�rke, Inna %A Terentyeva, Radmila %A da Cuñha, Daise N Q %A Sridhar, Arun %A Feldman, David S %A Hamlin, Robert L %A Carnes, Cynthia A %A Gy�rke, Sandor %D 2005 %J Proc. Natl. Acad. Sci. U. S. A. %K 16172392 Animals, Calcium Calcium, Cardiac Cardiac, Channel, Chronic Disease, Dogs, Extramural, Gov't, Heart, Low, Muscle Myocardium, Myocytes, N.I.H., Non-U.S. Output, P.H.S., Proteins, Receptor Release Research Reticulum, Ryanodine Sarcoplasmic Signaling, Support, U.S. %N 39 %P 14104--14109 %R 10.1073/pnas.0504298102 %T Abnormal intrastore calcium signaling in chronic heart failure. %U http://dx.doi.org/10.1073/pnas.0504298102 %V 102 %X Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intraluminal Ca in isolated cardiomyocytes and recordings from single-ryanodine receptor (RyR) channels reconstituted into lipid bilayers to investigate alterations in intracellular Ca handling in an experimental model of chronic HF. We found that diastolic free Ca inside the SR was dramatically reduced because of a Ca leak across the SR membrane, mediated by spontaneous local release events (Ca sparks), in HF myocytes. Additionally, the magnitudes of intrastore Ca depletion signals during global and focal Ca release events were blunted, and CaSR recovery was slowed after global but not focal Ca release in HF myocytes. At the single-RyR level, the sensitivity of RyRs to activation by luminal Ca was greatly enhanced, providing a molecular mechanism for the maintained potentiation of Ca sparks (and increased Ca leak) at reduced intra-SR Ca in HF. This work shows that the diminished SR Ca release characteristic of failing myocardium could be explained by increased sensitivity of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak and reduced intra-SR Ca.

@article{Kuba_2005_14104, abstract = {Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intraluminal [Ca] in isolated cardiomyocytes and recordings from single-ryanodine receptor (RyR) channels reconstituted into lipid bilayers to investigate alterations in intracellular Ca handling in an experimental model of chronic HF. We found that diastolic free [Ca] inside the SR was dramatically reduced because of a Ca leak across the SR membrane, mediated by spontaneous local release events (Ca sparks), in HF myocytes. Additionally, the magnitudes of intrastore Ca depletion signals during global and focal Ca release events were blunted, and [Ca]SR recovery was slowed after global but not focal Ca release in HF myocytes. At the single-RyR level, the sensitivity of RyRs to activation by luminal Ca was greatly enhanced, providing a molecular mechanism for the maintained potentiation of Ca sparks (and increased Ca leak) at reduced intra-SR [Ca] in HF. This work shows that the diminished SR Ca release characteristic of failing myocardium could be explained by increased sensitivity of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak and reduced intra-SR [Ca].}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Kubalova, Zuzana and Terentyev, Dmitry and Viatchenko-Karpinski, Serge and Nishijima, Yoshinori and Gy�rke, Inna and Terentyeva, Radmila and da Cuñha, Daise N Q and Sridhar, Arun and Feldman, David S and Hamlin, Robert L and Carnes, Cynthia A and Gy�rke, Sandor}, biburl = {https://www.bibsonomy.org/bibtex/2d5d85380d6b529759167997298f04c61/hake}, description = {The whole bibliography file I use.}, doi = {10.1073/pnas.0504298102}, file = {Kuba_2005_14104.pdf:Kuba_2005_14104.pdf:PDF}, interhash = {1f164edb576c173cfa7d320b7ecb62eb}, intrahash = {d5d85380d6b529759167997298f04c61}, journal = {Proc. Natl. Acad. Sci. U. S. A.}, key = 282, keywords = {16172392 Animals, Calcium Calcium, Cardiac Cardiac, Channel, Chronic Disease, Dogs, Extramural, Gov't, Heart, Low, Muscle Myocardium, Myocytes, N.I.H., Non-U.S. Output, P.H.S., Proteins, Receptor Release Research Reticulum, Ryanodine Sarcoplasmic Signaling, Support, U.S.}, month = Sep, number = 39, pages = {14104--14109}, pii = {0504298102}, pmid = {16172392}, timestamp = {2009-06-03T11:21:18.000+0200}, title = {Abnormal intrastore calcium signaling in chronic heart failure.}, url = {http://dx.doi.org/10.1073/pnas.0504298102}, volume = 102, year = 2005 }