Etiopathogenetic defect of malignant hyperthermia: Hypersensitive calcium-release channel of skeletal muscle sarcoplasmic reticulum

Abstract

Overwhelming clinical, physiological, pharmacological, and biochemical evidence indicates that MH occurs due to a genetic defect of intracellular calcium homeostasis in skeletal muscle. Specifically, the balance of data clearly and plausibly implicates the channel through which calcium is released from the terminal cisternae of sarcoplasmic reticulum as the site of the underlying molecular lesion of MH. This putative channel is commonly believed to be ligand-gated, that is, opened by the binding of specific agonists (Meisner, 1984). Apparently, the gating of the MH channel is abnormally sensitized, that is more tightly coupled than normal, to the binding of agonists such as calcium (and ATP). Consequently, the MH channel requires less trigger calcium or ATP for activation. Caffeine may act as weak agonist of the putative, purinergic (ATP) receptor of the ligand-gated calcium channel of the sarcoplasmic reticulum (Meisner, 1984). Persistent elevations of myoplasmic free calcium in the vicinity of the channel, which would be subliminal for normal muscle, may trigger massive and regenerative calcium-induced calcium-release in MHS muscle. Uncontrollable and sustained activation of the contractile apparatus and metabolic machinery follows. The source of the ‘trigger’ calcium may be the lumen of the transverse tubules via their voltage-gated calcium-channels (Ikemoto et al., 1984; Curtis & Catteral, 1984; Graf & Schatzmann, 1984), dislodged calcium from binding sites on the inner leaflet of the transverse tubular membrane (Frank, 1979; Curtis & Eisenberg, 1985), or the lumen of the terminal cisternae of sarcoplasmic reticulum via their ligand-gated calcium channels. Such persistent, but normally subliminal, elevations of ‘trigger’ calcium at the site of the calcium-release channel presumably occurs in MHS muscle with administration of potent volatile anesthetics, especially halothane, and depolarizing muscle relaxants, especially succinylcholine. The gaseous anesthetics apparently act indirectly on the calcium channel by virtue of their being potent but non-specific membrane perturbing agents (Ohnishi et al., 1986) which increase the passive permeability of the sarcoplasmic reticulum, and possibly surface membrane, to calcium. In individuals which are homozygous for the genetic defect the less potent muscle stimuli of anoxia, heat, and exertion may be sufficient to increase the local ‘trigger’ calcium concentration to a level resulting in uncontrollable calcium-release. Such homozygosity occurs rarely in people but commonly in swine due to inbreeding and the high frequency of the MH gene. Homozygosity for the MH gene may explain the occurrence of porcine (Topel, 1968), human (Wingard, 1974), and canine (O'Brien & Rand, 1985) stress syndromes: a double dosage of the genetic defect may render homozygotes hypersensitive to stimuli less potent than volatile anesthetics. Dantrolene, the MH-preventive and reversing (if administered early enough in the syndrome) drug, apparently acts by a different mechanism than drugs such as ruthenium red and the amide local anesthetics which appear to physically block the pore of the ligand-gated calcium channel (Ohnishi et al., 1986). Dantrolene's effect on the calcium channel is apparently indirect. It blocks the membrane-perturbing effects of halothane (Nelson & Denborough, 1977; Ohnishi et al., 1986) perhaps by ‘stabilizing’ muscle membranes and therefore their calcium channels (voltage-gated in transverse tubules and ligand-gated in terminal cisternae). However, this muscle relaxant is less effective at inhibiting the calcium-releasing effects of calcium or caffeine probably because these act directly on the calcium channel (Nelson & Denborough, 1977; Nelson, 1984; Britt et al., 1984; Araki et al., 1985; Ohnishi et al., 1986). Modelling the MH defect as a hypersensitive calcium-release channel also provides a plausible explanation for observations of gradations of susceptibility to triggering of MH for individuals and within populations (Gronert, 1980; Ellis & Heffron, 1985). This model predicts gradations due to gene dosage (homozygous versus heterozygous) as well as due to environmental, pharmacologic, and genetic factors which would compromise or challenge calcium homeostatic potential, such as: heat, anoxia, exertion, drugs which stimulate muscle, and other myopathies. Thus, MH is initiated due to a hypersensitive calcium-release mechanism of skeletal muscle sarcoplasmic reticulum. Malignant hyperthermia may be reversed by dantrolene and symptomatic treatment up until a critical irreversible point in the development of the syndrome. This point of irreversibility probably corresponds to the occurrence of significant degenerative structural and functional changes within the muscle fiber. Loss of calcium-sequestration capabilities by sarcoplasmic reticulum is likely the most important factor which contributes to the irreversibility of MH.