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Phosphoinositides and their phosphatases: Linking electrical and chemical signals in biological processes

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All living cells display a difference in electrical potential between their cytoplasm and the extracellular space. This difference in potential across the plasma membrane, commonly referred to as membrane potential, not only constitutes a signal of life, but it also constitutes a source of energy for the ...

All living cells display a difference in electrical potential between their cytoplasm and the extracellular space. This difference in potential across the plasma membrane, commonly referred to as membrane potential, not only constitutes a signal of life, but it also constitutes a source of energy for the translocation of many kinds of molecules in and out of the intracellular space. Changes in the membrane potential are related to a number of cellular events ranging from development to rapid electrical signaling in excitable tissues. For decades, the realm of cellular electrical activity has been limited to the action of ion channels and ionotropic ATPases and transporters. Indeed, the main molecular entities responsible for rapid signaling, such as action potentials and synaptic activity, have been identified. Yet, identification of the link between electrical activity at the plasma membrane and cell proliferation, differentiation and migration remains elusive. The quest to identify this link reached a turning point with the discovery of voltage-controlled enzymes. In particular, the voltage-sensitive phosphatase (VSP) has provided, for the first time, an example of a protein that conjugates electrical and enzymatic activities in a single molecular entity. Furthermore, the identification of VSP as a voltage-controlled enzyme has become a potential milestone in the elucidation of mechanisms underlying the modulation of cellular development by electrical activity.

VSPs are members of the protein tyrosine phosphatase (PTP) family that dephosphorylate phosphoinositides in a voltage-dependent manner. In turn, phosphoinositides are signaling lipids ubiquitously found in eukaryotes. These signaling molecules are involved in many processes including cell differentiation and survival, excitability, synaptic activity, fertilization, migration and regeneration. The most abundant phosphoinositide in the plasma membrane is known as phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2). This lipid is needed for the activity of a number of potassium-selective ion channels; depletion of PI(4,5)P2 causes the deactivation of some of these proteins. Another example is the phosphoinositide known as phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P3) which is considered a cell proliferation signal and its abundance is controlled by the concerted action of several enzymes including the tumor suppressor PTEN. Mutations that impair or abolish PTEN activity have been shown to be associated with several proliferative syndromes including cancer.

Given the importance of phosphoinositide-mediated signaling, it is essential to gain detailed insights into the balance between enzymes underlying the homeostasis of these signals. Thus, it is uncontestable that VSP may play a critical role in those signaling pathways involving phosphoinositides. Understanding the functioning of VSP is essential to unveiling the physiological relevance of these proteins.

The nascent field of voltage-sensitive phosphatases constitutes the first in its class, truly combining biochemical, optical and electrophysiological approaches to investigate the mechanisms of control and catalysis of these enzymes. Hence, the proposed topic will cover a range of topics involving VSP, including:
1. Molecular basis for electrical sensitivity
2. Mechanism of catalysis
3. Electrochemical coupling
4. Potential role of VSP in phosphoinositide signaling

The existence of putative non-channels, voltage-sensor containing proteins is now accepted. Thus, it is certainly daring, and yet not untenable to predict the existence of other proteins sharing similar molecular mechanisms. This topic may include other voltage-sensitive proteins.


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