alpha1S

Alpha1S, also known as Cav1.1, is the pore-forming alpha1 subunit of the skeletal muscle L-type voltage-gated calcium channel. It is encoded by the CACNA1S gene in humans and is a core component of the dihydropyridine receptor (DHPR) that resides in the transverse tubules of skeletal muscle cells. Alpha1S mediates the initial calcium entry in response to membrane depolarization and couples with the ryanodine receptor RyR1 to trigger calcium release from the sarcoplasmic reticulum, a process known as excitation-contraction coupling.

Functionally, alpha1S functions as the principal voltage-sensing and conducting subunit of Cav1.1 channels. Its activity is modulated by auxiliary subunits, including beta and alpha2delta proteins, which influence trafficking, gating, and current properties. In skeletal muscle, the conformational change of Cav1.1 upon depolarization is mechanically linked to RyR1, enabling the rapid rise in intracellular calcium that initiates muscle contraction.

Structurally, alpha1S is a large transmembrane protein comprising four homologous domains (I–IV), each with six transmembrane segments (S1–S6). The S4 segments act as voltage sensors, and the intracellular loops and termini support regulatory interactions with auxiliary subunits and signaling proteins. The N- and C-termini contain sites for post-translational modification and protein interactions that fine-tune channel behavior.

Genetically, CACNA1S mutations are associated with skeletal muscle disorders, most notably hypokalemic periodic paralysis type 1 and malignant hyperthermia susceptibility. Expression is highest in skeletal muscle, where alpha1S plays a central role in excitation-contraction coupling and muscle function.