Free radicals and calcium homeostasis: relevance to malignant hyperthermia?
The regulation of intracellular free calcium ions (Ca2+) in skeletal muscle at rest and during contraction depends on mechanisms such as Na(+)-Ca2+ exchangers, Ca(2+)-ATPases, and the voltage-sensitive ryanodine receptor. The susceptibility of these regulatory mechanisms to free-radical-mediated damage may be increased because of their location within the lipid membranes of sarcolemma, sarcoplasmic reticulum, and mitochondrion with resultant uncontrolled increases in myoplasmic Ca2+ concentration and cell death. The potentially fatal pharmacogenetic disorder, malignant hyperthermia (MH), is characterised by muscle rigidity, arrhythmias, lactic acidosis, and a rapid rise in body temperature. The sequence of events responsible for the MH syndrome remains uncertain, but it has been variously ascribed to faults in many of the Ca2+ regulatory mechanisms. In swine the condition is associated with a specific mutation in the ryanodine receptor, whereas in humans the syndrome is genetically heterogenous. Free-radical-mediated peroxidation of membrane lipids and proteins also results in the rapid efflux of Ca2+ from organelles, and the detection of products of free radical reactions in tissue from MH-susceptible individuals using electron spin resonance spectroscopy provides evidence for the involvement of free radicals in the MH syndrome.
Duthie
G G
GG
Rowett Research Institute, Bucksburn, Aberdeen, Scotland, UK.
Arthur
J R
JR
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005609:Free Radicals; D006706:Homeostasis; D006801:Humans; D008305:Malignant Hyperthermia / Q000209:etiology* / Q000378:metabolism; D009132:Muscles / Q000378:metabolism
D000975:Antioxidants; D005227:Fatty Acids; D005609:Free Radicals; D002118:Calcium