CACNA1S

CACNA1S is a gene that encodes the alpha-1S subunit of the skeletal muscle L-type voltage-gated calcium channel Cav1.1. The alpha-1S subunit forms the channel pore and, together with auxiliary subunits, mediates calcium influx in response to membrane depolarization. In skeletal muscle, Cav1.1 acts as the voltage sensor that triggers excitation-contraction coupling by initiating calcium release from the sarcoplasmic reticulum through the ryanodine receptor RyR1.

Expression of CACNA1S is highest in skeletal muscle, where the Cav1.1 channel localizes to the transverse tubules. The encoded protein is a large membrane protein (~2,100 amino acids) organized into four homologous domains (I–IV), each with six transmembrane segments that comprise the channel’s pore and voltage-sensing apparatus. It interacts with other channel partners, including beta and alpha-2/delta subunits, to regulate trafficking and function.

Clinical significance of CACNA1S genetic variation includes its role in hypokalemic periodic paralysis type 2 (HypoPP2), a disorder characterized by episodic muscle weakness associated with low serum potassium. Specific missense mutations, such as arginine-to-histidine substitutions, have been reported in affected individuals. Some CACNA1S variants have also been linked to susceptibility to malignant hyperthermia in certain families, although malignant hyperthermia is most commonly associated with variants in RYR1. Overall, CACNA1S mutations highlight the gene’s essential role in skeletal muscle excitation-contraction coupling and its contribution to inherited muscle disease.