Voltage Sensing And Transduction In Ci-VSP Protein
    By News Staff | September 14th 2007 08:52 PM | 2 comments | Print | E-mail | Track Comments
    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.


    Recently, new insights into the behavior of the Voltage Sensing Domain (VSD) of CI-VSP have been published in PNAS and Biophysical Journal. In these papers, the authors have shown the VSD to undergo relaxation after following prolonged depolarization. Interestingly, similar observations have been reported in regard of the slow inactivation of Voltage-Gated Channels (VGC), as they pointed out in these papers. This is a very important observation because Ci-VSP does not have a pore. In addition, the authors reported that a mutant of Ci-VSP stripped of its Phosphatase Domain (PD) also relaxes after prolonged depolarization. This clearly shows that the relaxation is a intrinsic of the VSD activity.

    In analogy with VGC, it is fair to say that, for many VGC, the open state is a transient states between the closed and the open states. An immediate implication rising from these observations is related to the crystal structure of VGC. Under crystallization conditions, the difference in electric potential across the protein is zero (depolarized). Therefore, the crystal structures show the VSD of channels in the inactivated (relaxed) states an not in the active states.

    in the previous comments, it should read "...the open state is a transient states between the closed and the relaxed states. "