Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes

被引:14
作者
Hartman, Jana M. [1 ]
Sobie, Eric A. [2 ]
Smith, Gregory D. [1 ]
机构
[1] Coll William & Mary, Dept Appl Sci, Williamsburg, VA 23187 USA
[2] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2010年 / 299卷 / 06期
基金
美国国家科学基金会;
关键词
calcium signaling; ryanodine receptor; leak; Markov chain; tetracaine; INDUCED CALCIUM-RELEASE; CHANNEL RYANODINE RECEPTOR; LOCAL-CONTROL MODELS; SARCOPLASMIC-RETICULUM; CARDIAC MYOCYTES; DYNAMIC REGULATION; INTEGRATIVE MODEL; LUMINAL CA2+; SUDDEN-DEATH; MARKOV-CHAIN;
D O I
10.1152/ajpheart.00293.2010
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Hartman JM, Sobie EA, Smith GD. Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes. Am J Physiol Heart Circ Physiol 299: H1996-H2008, 2010. First published September 17, 2010; doi: 10.1152/ajpheart.00293.2010.-Many issues remain unresolved concerning how local, subcellular Ca-2+ signals interact with bulk cellular concentrations to maintain homeostasis in health and disease. To aid in the interpretation of data obtained in quiescent ventricular myocytes, we present here a minimal whole cell model that accounts for both localized (subcellular) and global (cellular) aspects of Ca2+ signaling. Using a minimal formulation of the distribution of local [Ca2+] associated with a large number of Ca2+-release sites, the model simulates both random spontaneous Ca2+ sparks and the changes in myoplasmic and sarcoplasmic reticulum (SR) [Ca2+] that result from the balance between stochastic release and reuptake into the SR. Ca2+-release sites are composed of clusters of two-state ryanodine receptors (RyRs) that exhibit activation by local cytosolic [Ca2+] but no inactivation or regulation by luminal Ca2+. Decreasing RyR open probability in the model causes a decrease in aggregate release flux and an increase in SR [Ca2+], regardless of whether RyR inhibition is mediated by a decrease in RyR open dwell time or an increase in RyR closed dwell time. The same balance of stochastic release and reuptake can be achieved, however, by either high-frequency/short-duration or lowfrequency/long-duration Ca2+ sparks. The results are well correlated with recent experimental observations using pharmacological RyR inhibitors and clarify those aspects of the release-reuptake balance that are inherent to the coupling between local and global Ca2+ signals and those aspects that depend on molecular-level details. The model of Ca2+ sparks and homeostasis presented here can be a useful tool for understanding changes in cardiac Ca2+ release resulting from drugs, mutations, or acquired diseases.
引用
收藏
页码:H1996 / H2008
页数:13
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