Abstract
CaV1.1 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 CaV1.1-related diseases are muscle diseases and the molecular and cellular disease mechanisms relate to the dual functions of CaV1.1 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, CaV1.1-related myopathies, and myotonic dystrophy type 1. In addition, the CaV1.1 function in EC coupling is perturbed in Native American myopathy, arising from mutations in the CaV1.1-associated protein STAC3. Here, we first address general considerations concerning the possible roles of CaV1.1 in disease and then discuss the state of the art regarding the pathophysiology of the CaV1.1-related skeletal muscle diseases with an emphasis on molecular disease mechanisms.
Highlights
The skeletal muscle calcium channel (CaV1.1) is the prototypical voltage-gated calcium channel
Like CaV1.2, it does so by a functional interaction with the calcium release channel in the sarcoplasmic reticulum (SR), called the ryanodine receptor (RyR), which is a major source of the calcium transient in all muscles
Unlike the interaction between CaV1.2 and RyR2 in cardiac myocytes that depends on calcium-induced calcium release, in skeletal muscle, CaV1.1 and RyR1 interact physically with each other and this interaction is independent of the influx of calcium through the CaV1.1 channel [27]
Summary
The skeletal muscle calcium channel (CaV1.1) is the prototypical voltage-gated calcium channel. These leak currents cause muscle weakness due to the loss of excitability by inactivating NaV1.4 and at the same time trigger continuous depolarization-induced calcium release, consistent with the complex myopathy symptoms It would be of great interest, both for understanding the exact pathomechanism for R2142G and for better mechanistic understanding of CaV1.1 voltage-sensor function, if the biophysical properties of this disease mutation would be further analyzed in the new oocyte expression system. These two missense mutations suggest the intriguing possibility that mutations expected to perturb either the channel function or the EC coupling function of CaV1.1 both result in a similar disease phenotype This is unexpected in light of the evidence demonstrating that Ltype calcium currents are expandable for normal development and function of skeletal muscles in mice [19]. While an altered communication between CaV1.1 and RyR1 may lead to leaky release channels, the precise mechanisms how reduced EC coupling causes the plethora of symptoms of NAM still remain to be elucidated
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