Modulation of potassium channels by transmembrane auxiliary subunits via voltage-sensing domains

Voltage-gated K⁺ (K_V ) and Ca²⁺ -activated K⁺ (K_Ca ) channels are essential proteins for membrane repolarization in excitable cells. They also play important physiological roles in non-excitable cells. Their diverse physiological functions are in part the result of their auxiliary subunits. Auxiliary subunits can alter the expression level, voltage dependence, activation/deactivation kinetics, and inactivation properties of the bound channel. K_V and K_Ca channels are activated by membrane depolarization through the voltage-sensing domain (VSD), so modulation of K_V and K_Ca channels through the VSD is reasonable. Recent cryo-EM structures of the K_V or K_Ca channel complex with auxiliary subunits are shedding light on how these subunits bind to and modulate the VSD. In this review, we will discuss four examples of auxiliary subunits that bind directly to the VSD of K_V or K_Ca channels: KCNQ1-KCNE3, Kv4-DPP6, Slo1-β4, and Slo1-γ1. Interestingly, their binding sites are all different. We also present some examples of how functionally critical binding sites can be determined by introducing mutations. These structure-guided approaches would be effective in understanding how VSD-bound auxiliary subunits modulate ion channels.