Dual Effect of Phosphatidyl (4,5)-Bisphosphate PIP2 on Shaker K+ Channels

Phosphatidylinositol (4,5)-bisphosphate (PIP2) is a phospholipid of the plasma membrane that has been shown to be a key regulator of several ion channels. Functional studies and more recently structural studies of Kir channels have revealed the major impact of PIP2 on the open state stabilization. A...

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Bibliographic Details
Published in:The Journal of biological chemistry 2012-10, Vol.287 (43), p.36158-36167
Main Authors: Abderemane-Ali, Fayal, Es-Salah-Lamoureux, Zeineb, Delemotte, Lucie, Kasimova, Marina A., Labro, Alain J., Snyders, Dirk J., Fedida, David, Tarek, Mounir, Baró, Isabelle, Loussouarn, Gildas
Format: Article
Language:English
Subjects:
Biophysics
Electrophysiology
Gating
Molecular Biophysics
Phosphatidylinositol
Potassium Channels
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Summary:Phosphatidylinositol (4,5)-bisphosphate (PIP2) is a phospholipid of the plasma membrane that has been shown to be a key regulator of several ion channels. Functional studies and more recently structural studies of Kir channels have revealed the major impact of PIP2 on the open state stabilization. A similar effect of PIP2 on the delayed rectifiers Kv7.1 and Kv11.1, two voltage-gated K+ channels, has been suggested, but the molecular mechanism remains elusive and nothing is known on PIP2 effect on other Kv such as those of the Shaker family. 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 loss-of-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. Background: Phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates several voltage-gated K+ channels, but the molecular mechanism remains elusive. Results: PIP2 exerts on Shaker opposite effects on maximal current amplitude and activation voltage dependence. Conclusion: PIP2 stabilizes the gate in the open state and the voltage sensor in the resting state. Significance: This is the first description of an effect of PIP2 on voltage sensor movement.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.382085