Abstract
Dual Effect of Phosphatidyl (4,5)-Bisphosphate PIP2 on Shaker K+ Channels
Highlights
Phosphatidylinositol [4,5]-bisphosphate (PIP2) regulates several voltage-gated Kϩ channels, but the molecular mechanism remains elusive
By combining giant-patch ionic and gating current recordings in COS-7 cells, and voltage-clamp fluorimetry in Xenopus oocytes, both heterologously expressing the voltage-dependent Shaker channel, we show that PIP2 exerts 1) a gain-of-function effect on the maximal current amplitude, consistent with a stabilization of the open state and 2) a lossof-function effect by positive-shifting the activation voltage dependence, most likely through a direct effect on the voltage sensor movement, as illustrated by molecular dynamics simulations
We used Shaker and a combination of electrophysiology and voltage-clamp fluorimetry to better understand the molecular mechanism underlying the effect of PIP2 on the Kv channel activity
Summary
PIP2 exerts on Shaker opposite effects on maximal current amplitude and activation voltage dependence. By combining giant-patch ionic and gating current recordings in COS-7 cells, and voltage-clamp fluorimetry in Xenopus oocytes, both heterologously expressing the voltage-dependent Shaker channel, we show that PIP2 exerts 1) a gain-of-function effect on the maximal current amplitude, consistent with a stabilization of the open state and 2) a lossof-function effect by positive-shifting the activation voltage dependence, most likely through a direct effect on the voltage sensor movement, as illustrated by molecular dynamics simulations. In Kv channels and in voltage-gated Naϩ channels (Nav), positive residues of the voltage sensor S4 are close to the inner leaflet of the cell plasma membrane, especially in the closed state (20 –23) This raises the question whether or not PIP2 can modify the activity of these channels by direct modulation of the voltage-sensing mechanism. Gating current measurement and voltage-clamp fluorimetry suggest that a direct effect of PIP2 on the voltage-sensor movement underlies the PIP2-induced modification of the channel voltage dependence, but not of the current amplitude, suggesting two binding sites
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