The role of ion-regulatory membrane proteins of excitation-contraction coupling and relaxation in inherited muscle diseases

The excitation-contraction-relaxation cycle of skeletal muscle fibres depen ds on the finely tuned interplay between the voltage-sensing dihydropyridin e receptor, the junctional ryanodine receptor Ca2+-release channel and the sarcoplasmic reticulum Ca2+-ATPase. Inherited diseases of excitation-contra ction coupling and muscle relaxation such as malignant hyperthermia, centra l core disease, hypokalemic periodic paralysis or Brody disease are caused by mutations in these Ca2+-regulatory elements. Over twenty different mutat ions in the Ca2+-release channel are associated with susceptibility to the pharmacogenetic disorder malignant hyperthermia. Other mutations in the rya nodine receptor trigger central core disease. Primary abnormalities in the alpha-1 subunit of the dihydropyridine receptor underlie the molecular path ogenesis of both hypokalemic periodic paralysis and certain forms of malign ant hyperthermia. Some cases of the muscle relaxation disorder named Brody disease were demonstrated to be based on primary abnormalities in the Ca2+- ATPase. Since a variety of other sarcoplasmic reticulum proteins modulate t he activity of the voltage sensor, Ca2+-release channel and ion-binding pro teins, mutations in these Ca2+-regulatory muscle components might be the un derlying cause for novel, not yet fully characterized, genetic muscle disor ders. The cell biological analysis of knock-out mice has been helpful in ev aluating the biomedical consequences of defects in ion-regulatory muscle pr oteins.