Skeletal muscle CaV1.1 channelopathies

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.