Why the study?
CaV1.1 functions as a voltage sensor for skeletal muscle excitation-contraction coupling and an L-type calcium channel, and understanding the molecular pathophysiology underlying CaV1.1-related muscle diseases requires addressing its dual roles.
CaV1.1 channelopathies manifest as skeletal muscle diseases because CaV1.1 functions primarily as the voltage sensor for excitation-contraction coupling in skeletal muscle, with mutations often causing pathological leak currents (omega currents) rather than classical calcium channel dysfunction.
Challenges pore-centric models of Cav1.1 dysfunction; leaves open targeted research on EC coupling and omega currents in CACNA1S myopathies.
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.
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Bernhard E. Flucher (2020) studied this question.
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