Voltage-Controlled Enzymes: The New Janus Bifrons

The Ciona intestinalis voltage-sensitive phosphatase, Ci-VSP, was the first Voltage-controlled Enzyme (VEnz) proven to be under direct command of the membrane potential. The discovery of Ci-VSP conjugated voltage sensitivity and enzymatic activity in a single protein. These two facets of Ci-VSP activity have provided a unique model for studying how membrane potential is sensed by proteins and a novel mechanism for control of enzymatic activity. These facets make Ci-VSP a fascinating and versatile enzyme. Ci-VSP has a voltage sensing domain (VSD) that resembles those found in voltage-gated channels (VGC). The VSD resides in the N-terminus and is formed by four putative transmembrane segments. The fourth segment contains charged residues which are likely involved in voltage sensing. Ci-VSP produces sensing currents in response to changes in potential, within a defined range of voltages. Sensing currents are analogous to “gating” currents in VGC. As known, these latter proteins contain four VSDs which are entangled in a complex interaction with the pore domain – the effector domain in VGC. This complexity makes studying the basis of voltage sensing in VGC a difficult enterprise. In contrast, Ci-VSP is thought to be monomeric and its catalytic domain – the VSP’s effector domain – can be cleaved off without disrupting the basic electrical functioning of the VSD. For these reasons, VSPs are considered a great model for studying the activity of a VSD in isolation. Finally, VSPs are also phosphoinositide phosphatases. Phosphoinositides are signaling lipids found in eukaryotes and are involved in many processes, including modulation of VGC activity and regulation of cell proliferation. Understanding VSPs as enzymes has been the center of attention in recent years and several reviews has been dedicated to this area. Thus, this review will be focused instead on the other face of this true Janus Bifrons and recapitulate what is known about VSPs as electrically active proteins.