PIP2 controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 36; pp. E2399 - E2408
• Main Authors: Rodriguez-Menchaca, Aldo A, Adney, Scott K, Tang, Qiong-Yao, Meng, Xuan-Yu, Rosenhouse-Dantsker, Avia, Cui, Meng, Logothetis, Diomedes E
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 04-09-2012; National Academy of Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Crystallography, X-Ray; Ion Channel Gating - physiology; Kinetics; Membrane Potentials - physiology; Models, Molecular; Molecular Dynamics Simulation; Mutagenesis; Oocytes - metabolism; Patch-Clamp Techniques; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phospholipids - metabolism; PNAS Plus; Potassium Channels, Voltage-Gated - chemistry; Potassium Channels, Voltage-Gated - metabolism; Protein Subunits - metabolism; Xenopus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1207901109

Voltage-gated K + (Kv) channels couple the movement of a voltage sensor to the channel gate(s) via a helical intracellular region, the S4–S5 linker. A number of studies link voltage sensitivity to interactions of S4 charges with membrane phospholipids in the outer leaflet of the bilayer. Although the phospholipid phosphatidylinositol-4,5-bisphosphate (PIP 2 ) in the inner membrane leaflet has emerged as a universal activator of ion channels, no such role has been established for mammalian Kv channels. Here we show that PIP 2 depletion induced two kinetically distinct effects on Kv channels: an increase in voltage sensitivity and a concomitant decrease in current amplitude. These effects are reversible, exhibiting distinct molecular determinants and sensitivities to PIP 2 . Gating current measurements revealed that PIP 2 constrains the movement of the sensor through interactions with the S4–S5 linker. Thus, PIP 2 controls both the movement of the voltage sensor and the stability of the open pore through interactions with the linker that connects them.