Insights into the outward K+ currents-based gating mechanism of GIRK2 channel

GIRK channels have been involved in numerous physiological functions by regulating cellular excitability. Considering the characteristics of inward rectification, structure activity relationships of GIRK channels have been studied extensively based on the inward movements of ions. In contrast, the outward K+ currents based gating mechanism remains to be investigated in depth, although some drug molecules (dofetilide, cromakalim, and pinacidil etc.) exert medical effects by the current block or activation. In this study, the all-atom microsecond-scale molecular dynamics method was employed to explore the outward currents based gating mechanism of the GRK2 channels, which were modulated by different factors (Na+, Gβγ, and Na+-Gβγ). The results show that the Na+ and Gβγ subunits work together to activate the GIRK2 channel, in which Na+ predominantly regulates the G-loop gate, while Gβγ subunits mainly regulate the HBC gate. Our findings provide structural insights into the gating mechanism of GIRK channels and help to understand the pathology and pharmacodynamics mechanisms of drugs related to outflow currents.