The voltage sensor of voltage-gated ion channels is a conserved protein domain that senses millivolt changes in transmembrane potential, to regulate ion permeation through the channel. A recently discovered protein, Ci-VSP, has a voltage sensor that is coupled not to an ion channel but to a phosphatidylinositide phosphosphatase, the activity of which depends on membrane potential.

In a new paper published in The Journal of Physiology, Murata and Okamura, from the Okazaki Institute for Integrative Bioscience, examine a voltage-sensitive phosphatase that converts an electrical to a chemical signal; they directly demonstrate that the enzyme activity of Ci-VSP changes in a voltage-dependent manner through the operation of the voltage sensor.

Prior to this work, it was unclear which phosphoinositides were the major substrates of the phosphatase activity, and whether depolarisation or hyperpolarisation induced the phosphatase activity. By expressing phosphoinositide-specific sensors in Xenopus oocytes and applying both electrophysiology and imaging of phosphoinositides, it was shown that enzyme activity is activated upon depolarisation (not upon hyperpolarisation), and that levels of both PtdIns(4,5)P2 and PtsIns(3,4,5)P3 are regulated by the operation of voltage sensor.

“Our findings identify common principles of the voltage sensor shared between voltage-gated ion channels and the voltage-sensing phosphatase," comment the authors.

"There is no question that the VSP is a much simpler model than ion channels for understanding the mechanisms of voltage sensing, and understanding the VSP will provide insights into the function of ion channels as well. Such knowledge is critical for understanding general mechanisms of voltage sensing and many disorders coupled with altered membrane excitabilities. The VSP’s ability to tune phosphoinositide phosphatase activity by voltage will also serve as an important molecular tool to understand mechanisms of tumor suppressor phosphatase, PTEN, and other phosphatases that underlie carcinogenesis and metabolic disorders."

Article: “Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2”, by Yoshimichi Murata and Yasushi Okamura. 15 September 2007, The Journal of Physiology, 583.3, pp. 875–889.