A Common Kinetic Property of Mutations Linked to Episodic Ataxia Type 1 Studied in the Shaker Kv Channel.

(1) Background: Episodic ataxia type 1 is caused by mutations in the gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in Kv1.

Mode shift of the voltage sensors in Shaker K+ channels is caused by energetic coupling to the pore domain.

The voltage sensors of voltage-gated ion channels undergo a conformational change upon depolarization of the membrane that leads to pore opening. This conformational change can be measured as gating currents and is thought to be transferred to the pore domain via an annealing of the covalent link between voltage sensor and pore (S4-S5 linker) and the C terminus of the pore domain (S6). Upon prolonged depolarizations, the voltage dependence of the charge movement shifts to more hyperpolarized potentials.

An intersubunit interaction between S4-S5 linker and S6 is responsible for the slow off-gating component in Shaker K+ channels.

Voltage-gated ion channels are controlled by the membrane potential, which is sensed by peripheral, positively charged voltage sensors. The movement of the charged residues in the voltage sensor may be detected as gating currents. In Shaker K(+) channels, the gating currents are asymmetric; although the on-gating currents are fast, the off-gating currents contain a slow component.