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Researchers studied the mechanism by which the anticonvulsant Retigabine enhances the activity of K+ channels and found that the drug stabilizes on open state at resting membrane potentials.

This article is available online at http://www.jlr.org domain (VSD) homologous to the voltage sensors of voltage-gated ion channels and an intracellular C-terminal catalytic domain (CD) with high similarity to the tumor suppressor lipid phosphatase, PTEN ( Fig.1A ) ( 1 ). The enzymatic activity of the CD is controlled by the VSD via an intramolecular conformational switch ( 4, 5 ). At typical negative resting voltages, the CD is inactive and is rapidly activated at more-positive (depolarized) voltages. The VSP homologs characterized to date are phosphoinositide 5-phosphatases that degrade the major signaling phospholi pids PI(4,5)P 2 and PI(3,4,5)P 3 ( 2 ). Both phosphoinositides have key signaling roles in many cellular processes, including cell proliferation and differentiation, cytoskeletal dynamics, membrane traffi cking, and control of ion channels ( 6, 7 ). Although little is known to date about the biological functions of VSPs, the ubiquitous roles of phosphoinositides and of electrical signaling suggest a potential impact on a large spectrum of cellular processes.The principle of operation of VSPs was initially demonstrated for Ci-VSP, the prototypic VSP from the invertebrate chordate Ciona intestinalis . Subsequently, functional vertebrate VSPs have been identifi ed in fi shes and amphibia ( 8, 9 ). The VSP gene is also conserved in mammals ( 10 ). In general, there appears to be one VSP homolog in mammalian genomes; in the human genome, however, there are two expressed homologs, TPTE and TPTE2 (also termed TPIP) and additional pseudo-genes ( 10, 11 ). TPTE conforms to the architecture of VSPs, but it lacks phosphatase activity due to amino acid exchanges in the catalytic CX 5 R motif in the P-loop of the phosphatase domain The recent discovery of voltage-sensitive phosphatases (VSPs) ( 1 ) established a novel molecular principle of electrochemical coupling: VSPs directly mediate the degradation of phosphoinositides in response to depolarization of the membrane potential ( 2, 3 ). These so-far-unique electro-enzymes consist of a transmembrane voltage sensor