Kohout, Susy C.

Villalba-Galea, Carlos A.

English

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University of the PacificScholarly CommonsSchool of Pharmacy and Health Sciences FacultyArticlesThomas J. Long School of Pharmacy and HealthSciences7-8-2015Editorial: Phosphoinositides and theirphosphatases: Linking electrical and chemicalsignals in biological processesSusy C. KohoutMontana State University-Bozeman, skohout@montana.eduCarlos A. Villalba-GaleaVirginia Commonwealth University, cvillalbagalea@pacific.eduFollow this and additional works at: https://scholarlycommons.pacific.edu/phs-facarticlesPart of the Biochemistry, Biophysics, and Structural Biology Commons, Chemicals and DrugsCommons, and the Pharmacy and Pharmaceutical Sciences CommonsThis Article is brought to you for free and open access by the Thomas J. Long School of Pharmacy and Health Sciences at Scholarly Commons. It hasbeen accepted for inclusion in School of Pharmacy and Health Sciences Faculty Articles by an authorized administrator of Scholarly Commons. Formore information, please contact mgibney@pacific.edu.Recommended CitationKohout, S. C., & Villalba-Galea, C. A. (2015). Editorial: Phosphoinositides and their phosphatases: Linking electrical and chemicalsignals in biological processes. Frontiers in Pharmacology, 6, 142–142. DOI: 10.3389/fphar.2015.00142https://scholarlycommons.pacific.edu/phs-facarticles/321EDITORIALpublished: 08 July 2015doi: 10.3389/fphar.2015.00142Frontiers in Pharmacology | www.frontiersin.org 1 July 2015 | Volume 6 | Article 142Edited by:Jean-Yves Le Guennec,Université de Montpellier, FranceReviewed by:Sébastien Roger,University of Tours, France*Correspondence:Susy C. Kohout,skohout@montana.edu;Carlos A. Villalba-Galea,cavillalbaga@vcu.eduSpecialty section:This article was submitted toPharmacology of Ion Channels andChannelopathies,a section of the journalFrontiers in PharmacologyReceived: 11 June 2015Accepted: 26 June 2015Published: 08 July 2015Citation:Kohout SC and Villalba-Galea CA(2015) Editorial: Phosphoinositidesand their phosphatases: Linkingelectrical and chemical signals inbiological processes.Front. Pharmacol. 6:142.doi: 10.3389/fphar.2015.00142Editorial: Phosphoinositides and theirphosphatases: Linking electrical andchemical signals in biologicalprocessesSusy C. Kohout 1* and Carlos A. Villalba-Galea 2*1Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT, USA, 2Department of Physiologyand Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, USAKeywords: voltage-sensing phosphatase, membrane potential, cell signaling, phosphatidylinositols, ptenThe voltage-sensing phosphatase (VSP) has changed the way we think about both cellular electricalactivity and PIPs (phosphatidylinositol phosphates). Originally discovered in 1999 (Chen et al.,1999), these proteins were not recognized as electrically-controlled enzymes until 2005 (Murataet al., 2005). They constitute the first, and so far the only, example of an enzyme linking electricalsignals at the plasma membrane to the catalysis of PIPs (Murata et al., 2005), a ubiquitous family ofintracellular signaling molecules (Di Paolo and De Camilli, 2006; Balla, 2013). Before the discoveryof VSP, there were no known direct links between the two. Textbook examples would represent thisconnection with arrows, alluding to indirect or “yet-to-be-defined” signaling pathways. Now weknow that VSP serves as a direct connection between the electrical nature of the cell and PIPs, lipidsecond messengers that are critical for cell survival. However, many questions remain unansweredregarding VSP and its electrical regulation of cellular processes.With the discovery of VSP, the membrane potential must now be considered when studying PIPregulators. PIPs are involved in almost all aspects of cell physiology from survival, proliferation,and migration to pre-programed cell death (Di Paolo and De Camilli, 2006; Logothetis et al.,2010; Koch and Holt, 2012; Balla, 2013). For example, PIP concentrations are actively polarizedin migrating cells with phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) on the leading edgeand phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) on the lagging edge (Leslie et al., 2008).These gradients in the concentration of PIPs are necessary for activation of Rac and Rho leadingto cell motion. PIPs are also crucial for cell growth: PI(3,4,5)P3 activates the mTor cascadeleading to increased protein, membrane, and nucleic acid production (Dibble and Manning, 2013).Many human diseases have been associated with altered homeostasis of PIPs, including cancer,developmental disorders, and Alzheimer’s disease (Simpson and Parsons, 2001; McCrea and DeCamilli, 2009; Hakim et al., 2012). Though the physiological relevance of VSP is not yet defined, itis still crucial to human health to understand how PIPs are regulated and that now includes VSP.All cells have an asymmetric composition of ions across their plasma membrane, which,combined with selective permeabilities for these ions, results in a difference in the electricalpotential across their plasmamembrane. This difference, called themembrane potential, constitutesa form of cell signaling and a source of energy, both driving many biological processes. Thiselectrical potential difference powers neuronal excitability as well as more general processes likeproliferation, migration, and development (Levin, 2007; Sundelacruz et al., 2009; Yao et al., 2011).Regulation by the membrane potential has long been the sole purview of ion channels andtransporters and that has influenced what questions are asked regarding the changing potential.With our new knowledge of VSP, the changing membrane potential can directly signal the cellby modulating mTor and cell growth pathways, leading to abnormal growth or the M-current insympathetic ganglion, leading to hyperexcitability.Kohout and Villalba-Galea Voltage-controlled enzyme signalingThe articles in this Special Topic highlight several featuresof VSP including its unique activation, its similarities to otherenzymes and its use as a versatile tool to study other proteins.In the review article by Hobiger and Friedrich (2015, p. 20),the authors compare the structural similarities and differencesbetween the broader family of protein tyrosine phosphatasesand one of its newest members, VSP. They suggest a catalyticmechanism based on this comparison. Castle et al. (2015, p. 63)investigate the activation mechanism of VSP by probing the C2domain, the C-terminal domain of VSP that has been largelyunrecognized before the recent crystal structures showed a directcontribution of the C2 residue Y522 into the active site. The workbyMavrantoni et al. (2015, p. 68) explores the techniques that areused to test VSP and address some of their limitations includingthe need for expensive electrophysiology equipment as well as thelimitations of using channels as functional reporters. They taketheir methods and apply them to a chimera between the Cionaintestinalis VSP and human PTEN and show how the chimeraallows for the investigation of PTEN using standard techniquesbut with the advantage of regulated activation, voltage.Beyond the molecular mechanism underlying VSP activity,Mori et al. (2015, p. 22) review the use of VSP as a relativelysimple tool for manipulating PI(4,5)P2 concentrations in cells.They have used VSP to study the PI(4,5)P2 regulation of transientreceptor potential canonical channels involved in receptor-operated calcium currents. Along the same lines, Rjasanowet al. (2015, p. 127) use VSP as a tool that gives them precisecontrol over the PI(4,5)P2 concentrations in the membrane.These authors compared the relative PIP affinities betweenseveral ion channels. They also point out an important limitationthat the channels must already have a known specificity for aparticular PIP because VSP does not destroy PIPs in contrast tophospholipase C; instead, it generates multiple PIPs. All together,these articles underscore the features of VSP and expand ourunderstanding of its function and utility.Though VSP remains relatively unknown to many, thisnascent field has shown fast initial growth. The unique natureof these enzymes has inspired many to investigate theirproperties as well as take advantage of them. Many questionsremain unanswered regarding VSP such as how the voltagesensor couples to the enzyme and whether the phosphatasedomain is brought to the membrane for activation or whethera conformational change within the active site determinesactivation. We look forward to the studies that will address theseand the many other questions that persist in this exciting field.AcknowledgmentsThis work was supported by start-up funds from the MontanaState University Vice President for Research, Creativity andTechnology Transfer and NSF EPSCoR (EPS-1101342) to SK andCTSA - KL2TR000057 to CV.ReferencesBalla, T. (2013). Phosphoinositides: tiny lipids with giant impact on cell regulation.Physiol. Rev. 93, 1019–1137. doi: 10.1152/physrev.00028.2012Castle, P. M., Zolman, K. D., and Kohout, S. C. (2015). Voltage-sensingphosphatase modulation by a C2 domain. Front. Pharmacol. 6:63. doi:10.3389/fphar.2015.00063Chen, H., Rossier, C., Morris, M. A., Scott, H. S., Gos, A., Bairoch, A., et al. (1999).A testis-specific gene, TPTE, encodes a putative transmembrane tyrosinephosphatase and maps to the pericentromeric region of human chromosomes21 and 13, and to chromosomes 15, 22, and Y. Hum. Genet. 105, 399–409. doi:10.1007/s004390051122Dibble, C. C., and Manning, B. D. (2013). Signal integration by mTORC1coordinates nutrient input with biosynthetic output.Nat. Cell Biol. 15, 555–564.doi: 10.1038/ncb2763Di Paolo, G., and De Camilli, P. (2006). Phosphoinositides in cell regulation andmembrane dynamics. Nature 443, 651–657. doi: 10.1038/nature05185Hakim, S., Bertucci, M. C., Conduit, S. E., Vuong, D. L., and Mitchell, C. A. (2012).Inositol polyphosphate phosphatases in human disease. Curr. Top. Microbiol.Immunol. 362, 247–314. doi: 10.1007/978-94-007-5025-8_12Hobiger, K., and Friedrich, T. (2015). Voltage sensitive phosphatases: emergingkinship to protein tyrosine phosphatases from structure-function research.Front. Pharmacol. 6:20. doi: 10.3389/fphar.2015.00020Koch, M., and Holt, M. (2012). Coupling exo- and endocytosis: an essentialrole for PIP2 at the synapse. Biochim. Biophys. Acta 1821, 1114–1132. doi:10.1016/j.bbalip.2012.02.008Leslie, N. R., Batty, I. H., Maccario, H., Davidson, L., and Downes, C. P. (2008).Understanding PTEN regulation: PIP2, polarity and protein stability.Oncogene27, 5464–5476. doi: 10.1038/onc.2008.243Levin, M. (2007). Large-scale biophysics: ion flows and regeneration. Trends CellBiol. 17, 261–270. doi: 10.1016/j.tcb.2007.04.007Logothetis, D. E., Petrou, V. I., Adney, S. K., and Mahajan, R. (2010).Channelopathies linked to plasmamembrane phosphoinositides. Pflugers Arch.460, 321–341. doi: 10.1007/s00424-010-0828-yMavrantoni, A., Thallmair, V., Leitner, M. G., Schreiber, D. N., Oliver, D., andHalaszovich, C. R. (2015). A method to control phosphoinositides and toanalyze PTEN function in living cells using voltage sensitive phosphatases.Front. Pharmacol. 6:68. doi: 10.3389/fphar.2015.00068McCrea, H. J., and De Camilli, P. (2009). Mutations in phosphoinositidemetabolizing enzymes and human disease. Physiology 24, 8–16. doi:10.1152/physiol.00035.2008Mori, M. X., Itsuki, K., Hase, H., Sawamura, S., Kurokawa, T., Mori, Y., et al.(2015). Dynamics of receptor-operated Ca2+ currents through TRPC channelscontrolled via the PI(4,5)P2-PLC signaling pathway. Front. Pharmacol. 6:22.doi: 10.3389/fphar.2015.00022Murata, Y., Iwasaki, H., Sasaki, M., Inaba, K., and Okamura, Y. (2005).Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor.Nature 435, 1239–1243. doi: 10.1038/nature03650Rjasanow, A., Leitner, M. G., Thallmair, V., Halaszovich, C. R., and Oliver,D. (2015). Ion channel regulation by phosphoinositides analyzed withVSPs—PI(4,5)P2 affinity, phosphoinositide selectivity, and PI(4,5)P2pool accessibility. Front. Pharmacol. 6:127. doi: 10.3389/fphar.2015.00127Simpson, L., and Parsons, R. (2001). PTEN: life as a tumor suppressor. Exp. CellRes. 264, 29–41. doi: 10.1006/excr.2000.5130Sundelacruz, S., Levin, M., and Kaplan, D. L. (2009). Role of membrane potentialin the regulation of cell proliferation and differentiation. Stem Cell Rev. 5,231–246. doi: 10.1007/s12015-009-9080-2Yao, L., Pandit, A., Yao, S., and McCaig, C. D. (2011). Electric field-guided neuronmigration: a novel approach in neurogenesis. Tissue Eng. Part B Rev. 17,143–153. doi: 10.1089/ten.teb.2010.0561Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2015 Kohout and Villalba-Galea. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) or licensor are credited and that the original publication in thisjournal is cited, in accordance with accepted academic practice. No use, distributionor reproduction is permitted which does not comply with these terms.Frontiers in Pharmacology | www.frontiersin.org 2 July 2015 | Volume 6 | Article 142

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

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

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