γ subunits allow Slo potassium channels to open without an action potential. By cryo-EM structure determination, we show how γ1 binds the voltage-sensor domain (VSD) of Slo1. The kinked transmembrane helix and an extracellular hook of γ1 stabilize the VSD in its active conformation, while an intracellular polybasic stretch locally decreases the resting potential.

Mammalian Ca²⁺-dependent Slo K⁺ channels can stably associate with auxiliary γ subunits which fundamentally alter their behavior. By a so far unknown mechanism, the four γ subunits reduce the need for voltage-dependent activation and, thereby, allow Slo to open independently of an action potential. Here, using cryo-EM, we reveal how the transmembrane helix of γ1/LRRC26 binds and presumably stabilizes the activated voltage-sensor domain of Slo1. The activation is further enhanced by an intracellular polybasic stretch which locally changes the charge gradient across the membrane. Our data provide a possible explanation for Slo1 regulation by the four γ subunits and also their different activation efficiencies. This suggests a novel activation mechanism of voltage-gated ion channels by auxiliary subunits.