S1S4

S1S4 denotes the voltage-sensing domain formed by the first four transmembrane segments (S1 through S4) of many voltage-gated ion channels, including potassium (Kv), sodium (NaV), and calcium (CaV) channels. The S1–S4 domain sits within the channel’s core and serves to detect changes in membrane potential, translating voltage signals into conformational changes that regulate the pore formed by the S5–S6 segments.

Architecturally, S4 carries positively charged residues at regular intervals, which act as the primary gating charges. When the cell membrane depolarizes, S4 undergoes conformational rearrangements—often described in terms of translation and rotation—that are transmitted to the pore to promote opening. S1–S3 provide a structural scaffold that stabilizes S4 movements and modulate voltage sensitivity by contributing charged or polar residues and forming interactions with S4.

Distribution and relevance extend across major classes of voltage-gated channels. The S1S4 domain is a common feature in Kv, NaV, and CaV channels, though variations exist among subtypes and organisms. Understanding S1S4 is central to models of how voltage sensing couples to pore gating, with multiple conceptual frameworks proposed, including sliding-helix and paddle-type models that describe different aspects of S4 motion.

Methods used to study S1S4 include X-ray crystallography and cryo-electron microscopy to reveal structure, alongside electrophysiology and voltage-clamp fluorometry to link movement to function. The domain is a focus in research on channelopathies, as mutations in the S1S4 region can alter voltage sensing and are associated with conditions such as epilepsy, cardiac arrhythmias, and periodic paralysis.

Historically, the concept arose from studies of Shaker-family Kv channels in the late 20th century and has since become a foundational element in the understanding of voltage-dependent gating.