PIP2 controls voltage-sensor movement and pore opening of Kv channels through the S4-S5 linker.
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.
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Aldo A
AA
Rodriguez-Menchaca
Scott K
SK
Adney
Qiong-Yao
QY
Tang
Xuan-Yu
XY
Meng
Avia
A
Rosenhouse-Dantsker
Meng
M
Cui
Diomedes E
DE
Logothetis
D000818:Animals; D018360:Crystallography, X-Ray; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D014981:Xenopus
D019269:Phosphatidylinositol 4,5-Diphosphate; D010743:Phospholipids; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits