For a single or a group of Markov channels gating reversibly, distributions of open and closed times should be the sum of positively weighted decaying exponentials. Violation of this microscopic reversibility has been demonstrated previously on a number of occasions at the single channel level, and has been attributed to possible channel coupling to external sources of free energy. Here we show that distribution of durations of Ca(2+) release underlying Ca(2+) sparks in intact cardiac myocytes exhibits a prominent mode at approximately 8 ms. Analysis of the cycle time for repetitive sparks at hyperactive sites revealed no intervals briefer than approximately 35 ms and a mode at approximately 90 ms. These results indicate that, regardless of whether Ca(2+) sparks are single-channel or multi-channel in origin, they are generated by thermodynamically irreversible stochastic processes. In contrast, data from planar lipid bilayer experiments were consistent with reversible gating of RyR under asymmetric cis (4 microM) and trans Ca(2+) (10 mM), suggesting that the irreversibility for Ca(2+) spark genesis may reside at a supramolecular level. Modeling suggests that Ca(2+)-induced Ca(2+) release among adjacent RyRs may couple the external energy derived from Ca(2+) gradients across the SR to RyR gating in situ, and drive the irreversible generation of Ca(2+) sparks.
| Jiang, Dawei; Xiao, Bailong; Yang, Dongmei et al. (2004) RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci U S A 101:13062-7 |
| Zhu, Wei-Zhong; Wang, Shi-Qiang; Chakir, Khalid et al. (2003) Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. J Clin Invest 111:617-25 |
| Yang, Dongmei; Song, Long-Sheng; Zhu, Wei-Zhong et al. (2003) Calmodulin regulation of excitation-contraction coupling in cardiac myocytes. Circ Res 92:659-67 |
| Wang, Shi-Qiang; Song, Long-Sheng; Xu, Le et al. (2002) Thermodynamically irreversible gating of ryanodine receptors in situ revealed by stereotyped duration of release in Ca(2+) sparks. Biophys J 83:242-51 |
