EC.I.1 - Basıc aspects of excitation-contraction coupling and its relation to clinical disorders

Abstract

In response to excitation by motor neurons, skeletal muscle fibers develop trains of action potentials that spread along the sarcolemma and in depth along the transverse tubules. Depolarization induces a change in the configuration of a protein complex anchored in the transverse tubular membrane, the dihydropyridine receptor (DHPR), which gets open the ryanodine receptor (RyR) anchored in the membrane of the sarcoplasmic reticulum (SR) in charge of the release of Ca2+ that activates contraction. The succession of events from the action potential to the SR Ca2+ release is referred as the excitation-contraction coupling process. Relaxation of muscle fibers results from both the return of the fiber membrane potential to resting negative values and pumping of cytosolic Ca2+ back into the SR with the help of SR Ca2+-ATPases. The use of the voltage-clamp technique, the measurement of cytosolic or intra-SR Ca2+ changes, together with genetic approaches and recent developments of cryo-electron microscopy have all contributed to a better understanding of the basic molecular and cellular steps involved in the voltage controlled opening of the RyR by the DHPR but also allowed to uncover trans-sarcolemmal Ca2+ influx pathways and accessory proteins that participate in muscle Ca2+ homeostasis. Mutations in the genes encoding proteins involved in intracellular Ca2+ handling induce various muscle disorders such as Brody disease, malignant hyperthermia, central core disease or periodic paralysis with clinical features ranging from abnormal muscle stiffness to muscle weakness, paralysis or degeneration. Deciphering the pathophysiological mechanisms involved in these disorders is critical for the development of therapeutic strategies.