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Physiol Rev. 2009 Oct;89(4):1153-76. doi: 10.1152/physrev.00040.2008.

Calcium-induced calcium release in skeletal muscle.

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Saitama Medical University, Saitama, Japan.


Calcium-induced calcium release (CICR) was first discovered in skeletal muscle. CICR is defined as Ca2+ release by the action of Ca2+ alone without the simultaneous action of other activating processes. CICR is biphasically dependent on Ca2+ concentration; is inhibited by Mg2+, procaine, and tetracaine; and is potentiated by ATP, other adenine compounds, and caffeine. With depolarization of the sarcoplasmic reticulum (SR), a potential change of the SR membrane in which the luminal side becomes more negative, CICR is activated for several seconds and is then inactivated. All three types of ryanodine receptors (RyRs) show CICR activity. At least one RyR, RyR1, also shows non-CICR Ca2+ release, such as that triggered by the t-tubule voltage sensor, by clofibric acid, and by SR depolarization. Maximum rates of CICR, at the optimal Ca2+ concentration in the presence of physiological levels of ATP and Mg2+ determined in skinned fibers and fragmented SR, are much lower than the rate of physiological Ca2+ release. The primary event of physiological Ca2+ release, the Ca2+ spark, is the simultaneous opening of multiple channels, the coordinating mechanism of which does not appear to be CICR because of the low probability of CICR opening under physiological conditions. The coordination may require Ca2+, but in that case, some other stimulus or stimuli must be provided simultaneously, which is not CICR by definition. Thus CICR does not appear to contribute significantly to physiological Ca2+ release. On the other hand, CICR appears to play a key role in caffeine contracture and malignant hyperthermia. The potentiation of voltage-activated Ca2+ release by caffeine, however, does not seem to occur through secondary CICR, although the site where caffeine potentiates voltage-activated Ca2+ release might be the same site where caffeine potentiates CICR.

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