The sarcoplasmic reticulum has recently assumed a more prominent role with detailed knowledge of the structural process involved in excitation-contraction coupling, the mechanism by which nervous stimulation is immediately converted into a muscle contraction in a tightly controlled co-ordinated manner.
The sarcoplasmic invaginations (T tubules) are aligned closely with the terminal cisternas of the sarcoplasmic reticulum. The junctional gap between the two has only recently been described on a molecular basis. There appears to be a direct link, known as the triadic junction, composed of the dihydropyridine receptor on the T tubule and the ryanodine receptor on the sarcoplasmic reticulum. The dihydropyridine receptor consists of five subunits and is believed to act as a voltage sensor or slow Ca2+ channel. The ryanodine receptor, so called because it binds with high affinity with the plant alkaloid ryanodine, exists as a tetramer of identical subunits and is similar in structure to the nicotinic acetylcholine receptor. It consists of a 'foot structure' lying within the cytoplasm, with the remainder lying in the sarcoplasmic reticulum. It acts as a Ca2+ channel, with Ca2+ and ATP acting synergistically to open the channel while Mg 2+ and calmodulin inhibit opening.
It is believed that the altered kinetics of the ryanodine receptor Ca 2+ channel are due to both increased release of Ca2+ by small increases in the cytoplasmic Ca2+ concentration and a reduction in the inhibitory effects of high Ca 2+ concentrations.
Although the site of action of volatile anesthetic agents is uncertain, halothane can alter the voltage-dependent Ca 2+ channels and Ca2+ release from the sarcoplasmic reticulum and can affect the Ca2+-binding protein calmodulin which causes activation of many enzymes. It has recently been shown that propofol, which does not trigger malignant hyperthermia, does not stimulate ryanodine receptor activity but affects the dihydropyridine receptor and Ca 2+-ATPase in a similar manner to the inhalational anesthetics, supporting the hypothesis that the latter act on the ryanodine receptor ( Frueniefa/ 1995).
It is likely that excitation-contraction coupling occurs through a direct structural link rather than by a 'transmitter' effect using 1,4,5-trisphosphate. It is envisaged that the dihydropyridine receptor acts as a voltage sensor for changes in potential differences across the T-tubule membrane which in turn produce conformational changes in the ryanodine receptor, causing the Ca2+ channel to open. Although the precise mechanism of excitation-contraction coupling has yet to be verified, it is clear that the dihydropyridine and ryanodine receptors play crucial roles.
The role of the second messenger 1,4,5-trisphosphate in the pathophysiology of malignant hyperthermia is unclear; it has been postulated as a modulator of excitation-contraction coupling. As 1,4,5-trisphosphate levels are not altered after exposure to halothane, it seems unlikely that it has an important primary role in the onset and maintenance of malignant hyperthermia. A recent study suggests that malignant-hyperthermia-susceptible muscle is more responsive to 1,4,5-trisphosphate-induced Ca2+ release, which is prevented by dantrolene, than is normal muscle (Lopezelal 1995).
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