論文の公開元へCalcium-induced calcium release: 回顧と反省(筋生理の集い)
概要
Exactly fifty years ago, CICR (Ca-induced Ca release) was discovered through our analysis of mechanism of propagation of contraction in a skinned fiber evoked by a low concentration of caffeine in a medium containing a low concentration of EGTA. Inquiring into properties of CICR, then, it was found that from SR loaded with Ca up to the physiological level, 300μM or higher Ca2+ releases Ca, while lower concentration of Ca2+ was simply taken up to the SR, although physiological relevance of these experiments is questionable. Caffeine dose-dependently lowered Ca2+ concentration necessary for release of Ca. ATP strongly accelerated CICR. Procaine, known as caffeine inhibitor, inhibited CICR. These properties of CICR were found in early days, but genuine behavior of CICR had to wait our experiments in the absence of Ca pump activity. Thus, true Ca2+ concentration dependence of CICR was found to be bell-shaped so that higher concentrations of Ca2+ inhibit CICR. For the physiological significance of CICR we showed that CICR inhibitor procaine does not inhibit K-contracture, and concluded that CICR does not make any contribution to the activation of muscle contraction at all, too strong statement because of possible additional role of CICR in the activation. Apart from physiological role, we demonstrated that CICR plays an essential role in malignant hyperthermia. We proved that CICR in muscles from patients with malignant hyperthermia showed higher sensitivity and greater maximum response to Ca2+ than in normal muscle, and halothane, an anesthetic, also increased Ca2+ sensitivity and maximum response of CICR. Unlike skeletal muscle, physiological contraction of cardiac muscle is caused directly by CICR. Although at the beginning I myself asserted that, later a few experimental results led me to suspect that until recently. I regret my such poor insight in physiology.
