Acta Physiologica 2009; Volume 196, Supplement 671
Scandinavian Physiological Society’s Annual Meeting
CA2+ SPARKS AND CA2+ LEAK IN HEART
Abstract number: L35
Lederer1 WJ, Sobie2 EA, Lehnart3 S, Marks4 AR, Kass4 RS, Hagen1 BM, Gomez-Viquez1,5 L, Guatimosim1,6 S, Altamirano1 J
1Medical Biotechnology Center, University of Maryland Biotechnology Institute UMBI Baltimore, MD 2120, USA;
2Mt Sinai School of Medicine, New York, NY. USA;
3Georg August University School of Medicine, Goettingen, Germany;
4College of Physicians and Surgeons, Columbia University, New York, NY, USA;
CINVESTAV-IPN sede Sur, Mexico City, Mexico;
6Instituto de Ciencias Biologicas da UFMG, Belo Horizonte, Brazil. firstname.lastname@example.org
Ca2+ dependent cardiac arrhythmias are associated with cellular Ca2+ instability which has been attributed to excess Ca2+ within the sarcoplasmic reticulum (SR) or "[Ca2+]SR overload". Independent experiments attribute this arrhythmic tendency to SR Ca2+ "leak." Ironically, Ca2+ -dependent arrhythmias are observed in conditions where the steady-state [Ca2+]SR is low. This paradoxical result is observed in heart failure and in specific genetic arrhythmic conditions. In this presentation, experimental findings are combined with mathematical modeling results to suggest a resolution to the paradox.
The sarcoplasmic reticulum (SR) in heart muscle cells is the intracellular Ca2+ store that contributes most of the Ca2+ to the transient elevation of [Ca2+]i within the cytosol that occurs with each heartbeat and underlies contraction. The SR Ca2+ concentration ([Ca2+]SR) is a major factor that determines the level of the elevated [Ca2+]i during the transient. [Ca2+]SR is established primarily by two opposing processes -- the SR/ER Ca2+ ATPase (SERCA2a) that pumps Ca2+ into the SR and the SR Ca2+ loss ("leak") primarily through the SR Ca2+ release channels (ryanodine receptors, RyR2s). The RyR2s Ca2+ release channels are normally activated to release Ca2+ by cytosolic Ca2+ concentration ([Ca2+]i) but this process is highly regulated. While the low but measureable opening rate for RyR2s in heart cells under diastolic conditions leads to a low rate of diastolic Ca2+ sparks, the stereotyped SR Ca2+ release event in heart cell, this opening rate is subject to regulation. For example, the RyR2 sensitivity to [Ca2+]i is increased by elevated [Ca2+]SR and when this occurs the diastolic Ca2+ spark rate increases. When [Ca2+]SR is very high ("Ca2+ overload"), Ca2+ release instability is observed to occur and underlies the generation of propagated Ca2+ waves within myocytes that contribute to single cell "arrhythmogenesis". The RyR2s are broadly regulated by diverse processes including phosphorylation of RyR2 and association of diverse co-factors, cellular and SR lumenal proteins and the RyR2 redox state.
While increased RyR2 sensitivity to [Ca2+]i tends to increase SR Ca2+ instability at constant [Ca2+]SR, this increased RyR2 sensitivity of [Ca2+]i also tends to reduce SR Ca2+ by increasing the open probability of RyR2 and thereby increasing leak. Thus pump and leak of SR Ca2+ determine dynamically [Ca2+]SR. How these processes interact to enable Ca2+ instability arrhythmogenesis to develop in single cells under diverse yet relevant conditions is discussed.
Supported by the National Heart Lung and Blood Institute, the Leducq Fondation, the American Heart Association and the Maryland State Stem Cell Initiative.
To cite this abstract, please use the following information:
Acta Physiologica 2009; Volume 196, Supplement 671 :L35