Intracellular Calcium Release Channels in Muscles Related to Excitation-Contraction-Coupling and Malignant Hyperthermia
A plant alkaloid, ryanodine, was found to act specifically on intracellular Ca release channels, fixing them in the open state, only when the channels were open . Utilizing the specific action of ryanodine, the channel protein was isolated, purified [2–4], and sequenced . The purified channel protein showed all the properties of the Ca-induced Ca release (CICR) channel [3,4,6]; activation by Ca, acceleration of opening by ATP, inhibition of opening by Mg, and so on. Morphologically, the channel appeared to be very similar to the foot structure at the triad junction [2,4], which is considered to be the physiological Ca release channel. Curiously enough, however, CICR does not seem to be the mechanism of physiological Ca release. It is likely that the Ca release channel in skeletal muscle operates in different modes when stimulated through the physiological pathway (depolarization of the T-tubule membrane, probably through changes in voltage sensor molecules) and when stimulated by increased Ca ion concentration (CICR). Although the CICR opening mode does not seem to be important physiologically, it is important pathophysiologically, as in malignant hyperthermia (MH), and pharmacologically, as in caffeine contracture. These two opening modes are pharmacologically different; procaine and adenine inhibit the CICR mode, but not the physiological mode . An interesting agent is dantrolene; it inhibits both modes to an almost equal extent at 37°C, but at 20°C the agent does not inhibit the CICR mode at all, whereas it still effectively inhibits the physiological mode .
KeywordsSarcoplasmic Reticulum Release Channel Malignant Hyperthermia Malignant Hyperthermia Physiological Mode