[Frontiers in Bioscience 6, d65-74, January 1, 2001]

THE ROLE OF ION-REGULATORY MEMBRANE PROTEINS OF EXCITATION-CONTRACTION COUPLING AND RELAXATION IN INHERITED MUSCLE DISEASES

Gabriele R. Froemmingand Kay Ohlendieck

Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland

TABLE OF CONTENTS

1. Abstract
2. Excitation-contraction-relaxation cycle
2.1. Dihydropyridine receptor
2.2. Ryanodine receptor
2.3. Sarcoplasmic reticulum regulatory proteins
3. Hereditary muscle diseases
3.1. Malignant hyperthermia
3.2. Central core disease
3.3. Hypokalemic periodic paralysis
3.4. Brody disease
4. Conclusions and perspectives
5. Acknowledgments
6. References

1. ABSTRACT

The excitation-contraction-relaxation cycle of skeletal muscle fibres depends on the finely tuned interplay between the voltage-sensing dihydropyridine receptor, the junctional ryanodine receptor Ca2+-release channel and the sarcoplasmic reticulum Ca2+-ATPase. Inherited diseases of excitation-contraction coupling and muscle relaxation such as malignant hyperthermia, central core disease, hypokalemic periodic paralysis or Brody disease are caused by mutations in these Ca2+-regulatory elements. Over twenty different mutations in the Ca2+-release channel are associated with susceptibility to the pharmacogenetic disorder malignant hyperthermia. Other mutations in the ryanodine receptor trigger central core disease. Primary abnormalities in the alpha-1 subunit of the dihydropyridine receptor underlie the molecular pathogenesis of both hypokalemic periodic paralysis and certain forms of malignant 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 the activity of the voltage sensor, Ca2+-release channel and ion-binding proteins, mutations in these Ca2+-regulatory muscle components might be the underlying cause for novel, not yet fully characterized, genetic muscle disorders. The cell biological analysis of knock-out mice has been helpful in evaluating the biomedical consequences of defects in ion-regulatory muscle proteins.