Molecular mechanisms of Kir channel gating

Inward-rectifying K+ (Kir) channels are ubiquitously present in variety of cells and play an important role in maintaining resting membrane potential and supporting K+ homeostasis. They are an important family of K+ channels that connects cellular metabolism to membrane excitability, and exhibit complex lipid-protein interaction landscape. Dysfunction of Kir channels is, therefore, associated with multi-factorial diseases and are important drug targets. Recent high-resolution structural dynamics and functional studies of several Kir channels have significantly advanced our understanding of the mechanisms of voltage-dependent pore block and channel gating regulation mediated by lipids, and other modulators. In the present minireview, based on recent knowledge derived from prokaryotic and eukaryotic Kir channels, we highlight the binding sites of the channel for various ligands/modulators, and also provide an emerging model focusing on the structural rearrangements associated with the transition of the channel from the closed/deactivated to open/activated conformation during lipid-dependent gating, which should be broadly applicable to all Kir channels.