Malignant hyperthermia and excitation-contraction coupling

Malignant hyperthermia (MH) is a state of elevated skeletal muscle metaboli sm that may occur during general anaesthesia in genetically pre-disposed in dividuals. Malignant hyperthermia results from altered control of sarcoplas mic reticulum (SR) Ca2+ release. Mutations have been identified in MH-susce ptible (MHS) individuals in two key proteins of excitation-contraction (EC) coupling, the Ca2+ release channel of the SR, ryanodine receptor type 1 (R yR1) and the alpha1-subunit of the dihydropyridine receptor (DHPR, L-type C a2+ channel). During EC coupling, the DHPR senses the plasma membrane depol arization and transmits the information to the ryanodine receptor (RyR). As a consequence, Ca2+ is released from the terminal cisternae of the SR. One of the human MH-mutations of RyR1 (Arg614Cys) is also found at the homolog ous location in the RyR of swine (Arg615Cys). This animal model permits the investigation of physiological consequences of the homozygously expressed mutant release channel. Of particular interest is the question of whether v oltage-controlled release of Ca2+ is altered by MH-mutations in the absence of MH-triggering substances. This question has recently been addressed in this laboratory by studying Ca2+ release under voltage clamp conditions in both isolated human skeletal muscle fibres and porcine myotubes.