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Phosphoinositide 5-and 3-phosphatase activities of a voltage-sensing phosphatase in living cells show identical voltage dependence

Title
Phosphoinositide 5-and 3-phosphatase activities of a voltage-sensing phosphatase in living cells show identical voltage dependence
Author(s)
Keum, DongilKruse, MartinKim, Dong-IlHille, BertilSuh, Byung-Chang
Issued Date
2016-06-28
Citation
Proceedings of the National Academy of Sciences of the United States of America, v.113, no.26, pp.E3686 - E3695
Type
Article
Author Keywords
phosphoinositideDr-VSPCi-VSPPI(3,4,5)P-3PI(4,5)P-2
Keywords
ArticleCi-VSPControlled StudyDr-VSPEnzyme ActivityEnzyme MechanismEnzyme SpecificityFluorescence Resonance Energy TransferG(Q)-COUPLED RECEPTORLIPID PHOSPHATASENonhumanPhosphatasePhosphatidylinositol 3,4 BisphosphatePhosphatidylinositol 3,4,5 Trisphosphate 3 PhosphatasePhosphatidylinositol 4 Phosphate KinasePHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATEPhosphoinositidePhosphoinositide 3 PhosphatasePhosphoinositide 5 PhosphatasePHOSPHOLIPASE-CPI(3,4,5)P-3PI(4,5)P-2PLECKSTRIN-HOMOLOGY-DOMAINPriority JournalProtein DephosphorylationProtein ExpressionPTEN REGULATIONQUANTITATIVE PROPERTIESSEA-URCHIN EGGSSENSITIVE PHOSPHATASEUnclassified DrugVoltage Sensing PhosphataseZebra Fish
ISSN
0027-8424
Abstract
Voltage-sensing phosphatases (VSPs) are homologs of phosphatase and tensin homolog (PTEN), a phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3 ] 3-phosphatase. However, VSPs have a wider range of substrates, cleaving 3-phosphate from PI(3,4)P2 and probably PI(3,4,5)P3 as well as 5-phosphate from phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2 ] and PI(3,4,5)P3 in response to membrane depolarization. Recent proposals say these reactions have differing voltage dependence. Using Förster resonance energy transfer probes specific for different PIs in living cells with zebrafish VSP, we quantitate both voltagedependent 5- and 3-phosphatase subreactions against endogenous substrates. These activities become apparent with different voltage thresholds, voltage sensitivities, and catalytic rates. As an analytical tool, we refine a kinetic model that includes the endogenous pools of phosphoinositides, endogenous phosphatase and kinase reactions connecting them, and four exogenous voltage-dependent 5- and 3-phosphatase subreactions of VSP. We show that apparent voltage threshold differences for seeing effects of the 5- and 3-phosphatase activities in cells are not due to different intrinsic voltage dependence of these reactions. Rather, the reactions have a common voltage dependence, and apparent differences arise only because each VSP subreaction has a different absolute catalytic rate that begins to surpass the respective endogenous enzyme activities at different voltages. For zebrafish VSP, our modeling revealed that 3-phosphatase activity against PI(3,4,5)P3 is 55-fold slower than 5-phosphatase activity against PI(4,5)P2 ; thus, PI(4,5)P2 generated more slowly from dephosphorylating PI(3,4,5)P3 might never accumulate. When 5-phosphatase activity was counteracted by coexpression of a phosphatidylinositol 4-phosphate 5-kinase, there was accumulation of PI(4,5)P2 in parallel to PI(3,4,5)P3 dephosphorylation, emphasizing that VSPs can cleave the 3-phosphate of PI(3,4,5)P3 .
URI
http://hdl.handle.net/20.500.11750/5101
DOI
10.1073/pnas.1606472113
Publisher
National Academy of Sciences
Related Researcher
  • 서병창 Suh, Byung-Chang
  • Research Interests Molecular mechanisms of epilepsy and sensory pain transmission; Signaling mechanism of ion channel regulation and membrane excitability; 분자전기생리; 간질 및 통증의 분자적 기전 연구
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Department of Brain Sciences Laboratory of Brain Signal and Synapse Research 1. Journal Articles

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