title: Dynamic PIP2 interactions with voltage sensor elements contribute to KCNQ2 channel gating.
abstract: The S4 segment and the S4-S5 linker of voltage-gated potassium (Kv) channels are crucial for voltage sensing. Previous studies on the Shaker and Kv1.2 channels have shown that phosphatidylinositol-4,5-bisphosphate (PIP2) exerts opposing effects on Kv channels, up-regulating the current amplitude, while decreasing the voltage sensitivity. Interactions between PIP2 and the S4 segment or the S4-S5 linker in the closed state have been highlighted to explain the effects of PIP2 on voltage sensitivity. Here, we show that PIP2 preferentially interacts with the S4-S5 linker in the open-state KCNQ2 (Kv7.2) channel, whereas it contacts the S2-S3 loop in the closed state. These interactions are different from the PIP2-Shaker and PIP2-Kv1.2 interactions. Consistently, PIP2 exerts different effects on KCNQ2 relative to the Shaker and Kv1.2 channels; PIP2 up-regulates both the current amplitude and voltage sensitivity of the KCNQ2 channel. Disruption of the interaction of PIP2 with the S4-S5 linker by a single mutation decreases the voltage sensitivity and current amplitude, whereas disruption of the interaction with the S2-S3 loop does not alter voltage sensitivity. These results provide insight into the mechanism of PIP2 action on KCNQ channels. In the closed state, PIP2 is anchored at the S2-S3 loop; upon channel activation, PIP2 interacts with the S4-S5 linker and is involved in channel gating.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Qiansen
authors.initials: Q
authors.lastname: Zhang
authors.forename: Pingzheng
authors.initials: P
authors.lastname: Zhou
authors.forename: Zhuxi
authors.initials: Z
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Gao
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018076:DNA, Complementary / Q000235:genetics; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D051658:KCNQ2 Potassium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011487:Protein Conformation; D014982:Xenopus laevis
chemical_list: D018076:DNA, Complementary; D051658:KCNQ2 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate
keywords: M current; lipid; membrane; membrane protein