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Biophys J, July 2002, p. 242-251, Vol. 83, No. 1
*Laboratory of Cardiovascular Sciences, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224;
Department of Biochemistry and Biophysics, University of
North Carolina, Chapel Hill, North Carolina 27599; and
Department of Molecular Biophysics and Physiology, Rush
University, Chicago, Illinois 60612 USA
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 Ca2+ release
underlying Ca2+ sparks in intact cardiac myocytes exhibits
a prominent mode at ~8 ms. Analysis of the cycle time for repetitive
sparks at hyperactive sites revealed no intervals briefer than ~35 ms
and a mode at ~90 ms. These results indicate that, regardless of
whether Ca2+ 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 µM) and trans Ca2+
(10 mM), suggesting that the irreversibility for Ca2+ spark
genesis may reside at a supramolecular level. Modeling suggests that
Ca2+-induced Ca2+ release among adjacent RyRs
may couple the external energy derived from Ca2+ gradients
across the SR to RyR gating in situ, and drive the irreversible
generation of Ca2+ sparks.
Biophys J, July 2002, p. 242-251, Vol. 83, No. 1
© 2002 by the Biophysical Society 0006-3495/02/07/242/10 $2.00
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