A sodium-mediated structural switch that controls the sensitivity of Kir channels to PIP2

Inwardly rectifying potassium (Kir) channels are gated by the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2). Among them, Kir3 channel gating requires additional molecules, such as the βγ subunits of G proteins or intracellular sodium. Using an interactive computational-experimental approach, we show that sodium sensitivity of Kir channels involves the side-chains of an aspartate and a histidine located across from each other in a critical loop in the cytosolic domain, as well as the backbone carbonyls of two additional residues and a water molecule. The location of the coordination site in the vicinity of a conserved arginine shown to affect channel-PIP2 interactions suggests that sodium triggers a structural switch that frees the critical arginine. Mutations of the aspartate and the histidine that affect sodium sensitivity also enhance the channel’s sensitivity to PIP2. Furthermore, based on the molecular characteristics of the coordination site, we identify and confirm experimentally a novel sodium-sensitive phenotype in Kir5.1. Kir channels are important in setting the resting membrane potential and modulating membrane excitability1–3. A common feature of Kir channels and many other ion channel