Voltage gated K⁺ channels are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potential, regulation of Ca²⁺ signaling and cell volume to driving cellular proliferation and migration.

K_V2.1 consists of four α-subunits, each containing six transmembrane α-helical segments, S1-S6, and a membrane-re-entering P-loop, which are arranged circumferentially around a central pore. This ion conduction pore is lined by four S5-P-S6 sequences. The four S1–S4 segments, each containing four positively charged arginine residues in the S4 helix, act as voltage sensor domains and “gate” the pore by “pulling” on the S4–S5 linker.

K_V2.1, encoded by the KCNB1 gene, is a classical delayed rectifier channel that is involved in neuronal repolarization. Its function can be diversified through heteromultimerization with “silent” K_V units, which modify inactivation, trafficking, drug sensitivity and expression.

Inhibition of K_V2.1 in pancreatic β-cells enhances insulin secretion, suggesting a potential therapeutic strategy for type 2 diabetes. This effect is presumed to occur through non-conducting functions - namely, a physical interaction with syntaxin (a component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex) that facilitates vesicle fusion¹.

Recently, a “de novo” pathogenic K_V2.1 variant was discovered in a family suffering from idiopathic epileptic encephalopathy. This variant is a missense mutation in the coding region of the KCNB1 gene. Expression of the V378A variant results in voltage-activated currents that are sensitive to the selective K_V2 channel blocker guangxitoxin-1E. Currents through the mutant channel are non-selective among monovalent cations².