Another story of arginines in voltage sensing: the role of phosphoinositides in coupling voltage sensing to enzyme activity

The sensing of transmembrane electrical potential has long been thought to be unique to voltage-gated ion channels. Recently, however, transmembrane voltage has been shown to regulate the enzymatic activity of a protein, called voltage-sensing phosphatase (VSP), that is conserved across diverse phyla (Murata et al., 2005; Murata and Okamura, 2007; Hossain et al., 2008). In VSP, the voltage sensor domain is linked not to a pore domain but to a phosphoinositide phosphatase with remarkable similarity to the tumor suppressor protein PTEN (phosphatase and tensin homologue deleted on chromosome 10). The PTEN-like domain of VSP dephosphorylates phosphoinositides, a species of negatively charged lipids that acts as signaling molecules for diverse cellular events. VSP shows asymmetrical capacitative currents derived from the motion of its voltage sensor domain, similar to the gating currents of voltagegated ion channels (Murata et al., 2005; Murata and Okamura, 2007; Hossain et al., 2008). It has been established that the motion of the voltage sensor drives phosphatase activity as detected by the changes of activities of potassium channels that report the concentration of PI(4,5)P2 (Murata et al., 2005; Murata and Okamura, 2007). VSP most likely operates as a monomer, as revealed by single-molecule imaging (Kohout et al., 2008). Therefore, VSP potentially provides an excellent model to understand mechanisms of coupling between a voltage sensor and an effector (Okamura, 2007; Okamura et al., 2009). Valuable clues to the coupling mechanisms of VSP come from extensive biochemical (Maehama et al., 2001) and x-ray crystallography (Lee et al., 1999) studies of PTEN. To function, phosphoinositide phosphatases need to come physically close to membranes to access their substrates. Proximity is achieved in several ways in different proteins: having an N-terminal transmembrane segment (Pagliarini et al., 2004), binding to other membrane-associated proteins, or association to membrane via a motif or domain with affinity for lipid (Begley and Dixon, 2005). PTEN contains two regions that mediate membrane targeting: a PI(4,5)P2-binding motif at the N terminus and a C2 domain (Fig. 1; Lee