Dynamic PIP₂ interactions with voltage sensor elements contribute to KCNQ2 channel gating

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 50; pp. 20093 - 20098
• Main Authors: Zhang, Qiansen, Zhou, Pingzheng, Chen, Zhuxi, Li, Min, Jiang, Hualiang, Gao, Zhaobing, Yang, Huaiyu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10-12-2013; National Acad Sciences
• Subjects: Animals; Biological Sciences; CHO Cells; Cricetinae; Cricetulus; DNA, Complementary - genetics; Ion Channel Gating - genetics; Ion Channel Gating - physiology; KCNQ2 Potassium Channel - chemistry; KCNQ2 Potassium Channel - genetics; KCNQ2 Potassium Channel - metabolism; Models, Molecular; Molecular Dynamics Simulation; Mutagenesis; Patch-Clamp Techniques; Phosphatidylinositol 4,5-Diphosphate - metabolism; Protein Conformation; Xenopus laevis; M current; membrane protein; membrane; lipid
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1312483110

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 (PIP ₂) exerts opposing effects on Kv channels, up-regulating the current amplitude, while decreasing the voltage sensitivity. Interactions between PIP ₂ and the S4 segment or the S4–S5 linker in the closed state have been highlighted to explain the effects of PIP ₂ on voltage sensitivity. Here, we show that PIP ₂ 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 PIP ₂–Shaker and PIP ₂–Kv1.2 interactions. Consistently, PIP ₂ exerts different effects on KCNQ2 relative to the Shaker and Kv1.2 channels; PIP ₂ up-regulates both the current amplitude and voltage sensitivity of the KCNQ2 channel. Disruption of the interaction of PIP ₂ 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 PIP ₂ action on KCNQ channels. In the closed state, PIP ₂ is anchored at the S2–S3 loop; upon channel activation, PIP ₂ interacts with the S4–S5 linker and is involved in channel gating.