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

Abstract

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)P2). Using planar lipid bilayers we show that Kir2.2 exhibits bursts of openings separated by long quiescent inter-burst periods. Increasing PI(4,5)P2 concentration shortens the Kir2.2 inter-burst duration and lengthens the burst duration without affecting dwell times within a burst. From this, we propose that burst and inter-burst durations correspond to the CTD-docked and CTD-undocked conformations observed in the presence and absence of PI(4,5)P2 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)P2 but cannot activate Kir2.2 without the 5 phosphate. PI(4)P, which is directly interconvertible to and from PI(4,5)P2, might thus be a regulator of Kir channels in the plasma membrane.