Abnormal intrastore calcium signaling in chronic heart failure.
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].
Kubalova
Zuzana
Z
Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, USA.
Terentyev
Dmitry
D
Viatchenko-Karpinski
Serge
S
Nishijima
Yoshinori
Y
Györke
Inna
I
Terentyeva
Radmila
R
da Cuñha
Daise N Q
DN
Sridhar
Arun
A
Feldman
David S
DS
Hamlin
Robert L
RL
Carnes
Cynthia A
CA
Györke
Sandor
S
D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D020013:Calcium Signaling; D002303:Cardiac Output, Low / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D004285:Dogs; D006321:Heart / Q000503:physiopathology; D009124:Muscle Proteins / Q000032:analysis / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*
D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium