S1S6

S1S6 is a shorthand used in biophysics and membrane biology to denote the six transmembrane helices labeled S1 through S6 that compose each homologous domain of voltage-gated ion channels. In most channels, including voltage-gated potassium (Kv), sodium (Nav), and calcium (Cav) channels, a single functional alpha subunit contains four such domains (DI–DIV), each with its own S1–S6 set. The channel's pore is formed by the S5–S6 helices and their connecting P-loop, while the S1–S4 helices constitute the voltage-sensing domain.

Within a domain, S4 carries regularly spaced positive charges and acts as the primary voltage sensor. Movement of S4 in response to changes in membrane potential drives conformational changes that open or close the activation gate formed by S6 helices. The S1–S3 segments support the structural framework and participate in coupling the sensing domain to the pore.

The term S1S6 emphasizes topology rather than a separate protein. It is used in structural models, electrophysiology simulations, and discussions of gating mechanics to reference the entire transmembrane region of a domain (S1 through S6).

Mutations in residues across S1–S6 can alter voltage sensitivity, gating kinetics, or ion selectivity and are implicated in channelopathies. Pharmacological agents such as pore-blocking drugs interact with regions formed by S5–S6, while modulators may affect the voltage-sensing S1–S4 segments.