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Calcium-Induced Calcium Release in Skeletal Muscle

Saitama Medical University, Kawagoe, 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.

² In intact mammalian fibers, procaine strongly inhibits physiological Ca²⁺ release (81), but in peeled fibers, procaine was reported to not inhibit Ca²⁺ release induced by t-tubule depolarization (39).

³ Pape et al. (211) estimated the concentration of RyR channels to be 0.27 µM in reference to the myoplasm, assuming that one foot structure at the junctional region (77) corresponds to one channel. However, Felder and Franzini-Armstrong (64) later showed that the foot structures facing t-tubule membrane, coupled or uncoupled with DHPR, are all RyR and that RyRβ channels, the number of which is almost equal to that of RyR, are located at the parajunctional region. Therefore, the concentration of RyR channels in amphibian skeletal muscle should be twice the previous estimation, 0.55 µM. In mammalian muscles, the content of RyR3 is generally a few percent at most, but because each sarcomere has two t-tubules in mammals, unlike in amphibians, the estimated concentration could also be 0.55 µM.

⁴ A concentration of 0.55 µmol/l muscle is equivalent to 3.3 x 10¹⁷ channels/l muscle. If P_o is 0.01, and each open channel carries 0.5 pA, which is (0.5 x 10^–12 [C/s]/2 x 9.65 x 10⁴ [C/mol]) = 0.26 x 10^–20 mol Ca²⁺/ms, the rate of Ca²⁺ release is 8.58 x 10^–6 mol·l muscle^–1·ms^–1.

⁵ The maximum rate of CICR is 0.02%/ms (see sect. IIIB6), or 0.4 µM/ms if the Ca²⁺ content in the SR is assumed to be 2 mol/l muscle. If the Ca²⁺ current through RyR channels is assumed to be 0.5 pA (121), which is 0.26 x 10^–20 mol Ca²⁺·ms^–1·channel^–1, then 1.54 x 10¹⁴ channels/l muscle, which is 2.6 x 10^–10 mol/l muscle, are open. If the density of RyR channels is assumed to be 0.55 µM (see sect. IIIB6), then 0.05% of channels are open.