Abstract
Ca(V)1.1 is specifically expressed in skeletal muscle where it functions as voltage sensor of skeletal muscle excitation-contraction (EC) coupling independently of its functions as L-type calcium channel. Consequently, all known Ca(V)1.1-related diseases are muscle diseases and the molecular and cellular disease mechanisms relate to the dual functions of Ca(V)1.1 in this tissue. To date, four types of muscle diseases are known that can be linked to mutations in the CACNA1S gene or to splicing defects. These are hypo- and normokalemic periodic paralysis, malignant hyperthermia susceptibility, Ca(V)1.1-related myopathies, and myotonic dystrophy type 1. In addition, the Ca(V)1.1 function in EC coupling is perturbed in Native American myopathy, arising from mutations in the Ca(V)1.1-associated protein STAC3. Here, we first address general considerations concerning the possible roles of Ca(V)1.1 in disease and then discuss the state of the art regarding the pathophysiology of the Ca(V)1.1-related skeletal muscle diseases with an emphasis on molecular disease mechanisms.