Abnormal Intrastore Calcium Signaling in Chronic Heart Failure

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 39; pp. 14104 - 14109
• Main Authors: Kubalova, Zuzana, Terentyev, Dmitry, Viatchenko-Karpinski, Serge, Nishijima, Yoshinori, Györke, Inna, Terentyeva, Radmila, Daise N. Q. da Cuñha, Sridhar, Arun, Feldman, David S., Hamlin, Robert L., Carnes, Cynthia A., Györke, Sandor, Latorre, Ramon
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.09.2005; National Acad Sciences
• Subjects: Anatomy & physiology; Animals; Biological Sciences; Calcium; Calcium - analysis; Calcium - metabolism; Calcium Signaling; Canines; Cardiac Output, Low - metabolism; Cardiac Output, Low - pathology; Cardiac Output, Low - physiopathology; Chronic Disease; Dogs; Fluorescence; Heart; Heart - physiopathology; Heart failure; Imaging; Lipid bilayers; Muscle Proteins - analysis; Muscle Proteins - metabolism; Myocardium; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Physiological regulation; Receptors; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - chemistry; Sarcoplasmic Reticulum - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0504298102

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 singleryanodine 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]SRrecovery 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].