Phosphoinositide Phosphatases: Emerging Roles As Voltage Sensors?

Schematic of potential mechanisms of action of Ci-VSP. The sensor portion of Ci-VSP is shown as dark blue barrels labeled S1–S4 and the phosphatase domain by a light-blue box (inactive) or oval (active). PI(3,4,5)P₃ is indicated by red circles whereas PI(4,5)P₂ is represented by green circles. The red ovals represent an inwardly rectifying potassium channel (Kir) and the lightning bolt indicates a change in membrane potential and/or conformation. In the absence of a change in membrane shape or potential, Ci-VSP is in its inactive state and the nearby K⁺ channel is not active. A change in the membrane (lightning bolt) is sensed by the S4 transmembrane domain of Ci-VSP, which then undergoes a conformational change resulting in the activation of the phosphatase. This could occur either by repositioning the phosphatase domain closer to its substrate and/or by changing its conformation thereby activating it. In either case, the localized concentration of PI(4,5)P₂ (green circles) in the membrane is increased leading to increased activity of a closely juxtaposed channel.