Correlation between structure and function in phosphatidylinositol lipid–dependent Kir2.2 gating

Inward rectifier K(+)(Kir) channels regulate cell membrane potential. Different Kir channels respond to unique ligands, but all are regulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)). Using planar lipid bilayers, we show that Kir2.2 exhibits bursts of openings separated by long quiescent interburst periods. Increasing PI(4,5)P(2) concentration shortens the Kir2.2 interburst duration and lengthens the burst duration without affecting dwell times within a burst. From this, we propose that burst and interburst durations correspond to the cytoplasmic domain (CTD)–docked and CTD-undocked conformations observed in the presence and absence of PI(4,5)P(2) in atomic structures. We also studied the effect of different phosphatidylinositol lipids on Kir2.2 activation and conclude that the 5′ phosphate is essential to Kir2.2 pore opening. Other phosphatidylinositol lipids can compete with PI(4,5)P(2) but cannot activate Kir2.2 without the 5′ phosphate. PI(4)P, which is directly interconvertible to and from PI(4,5)P(2), might thus be a regulator of Kir channels in the plasma membrane.