Cryo-EM structure of the Slo1 potassium channel with the auxiliary γ1 subunit suggests a mechanism for depolarization-independent activation

Mammalian Ca2+-dependent Slo K+ channels can stably associate with auxiliary gamma subunits which fundamentally alter their behavior. By a so far unknown mechanism, the four gamma 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 gamma 1/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 gamma subunits and also their different activation efficiencies. This suggests a novel activation mechanism of voltage-gated ion channels by auxiliary subunits. gamma subunits allow Slo potassium channels to open without an action potential. By cryo-EM structure determination, we show how gamma 1 binds the voltage-sensor domain (VSD) of Slo1. The kinked transmembrane helix and an extracellular hook of gamma 1 stabilize the VSD in its active conformation, while an intracellular polybasic stretch locally decreases the resting potential. image