PIP2 hydrolysis underlies agonist‐induced inhibition and regulates voltage gating of two‐pore domain K+ channels

Abstract

Two‐pore (2‐P) domain potassium channels are implicated in the control of the resting membrane potential, hormonal secretion, and the amplitude, frequency and duration of the action potential. These channels are strongly regulated by hormones and neurotransmitters. Little is known, however, about the mechanism underlying their regulation. Here we show that phosphatidylinositol 4,5‐bisphosphate (PIP 2) gating underlies several aspects of 2‐P channel regulation. Our results demonstrate that all four 2‐P channels tested, TASK1, TASK3, TREK1 and TRAAK are activated by PIP 2. We show that mechanical stimulation may promote PIP 2 activation of TRAAK channels. For TREK1, TASK1 and TASK3 channels, PIP 2 hydrolysis underlies inhibition by several agonists. The kinetics of inhibition by the PIP 2 scavenger polylysine, and the inhibition by the phosphatidylinositol 4‐kinase inhibitor wortmannin correlated with the level of agonist‐induced inhibition. This finding suggests that the strength of channel PIP 2 interactions determines the extent of PLC‐induced inhibition. Finally, we show that PIP 2 hydrolysis modulates voltage dependence of TREK1 channels and the unrelated voltage‐dependent KCNQ1 channels. Our results suggest that PIP 2 is a common gating molecule for K+ channel families despite their distinct structures and physiological properties.