Phosphatidylinositol 4-phosphate is a major source of GPCR-stimulated phosphoinositide production.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Association for the Advancement of Science
    • Subject Terms:
      Diglycerides/*metabolism ; Phosphatidylinositol Phosphates/*metabolism ; Phosphatidylinositols/*metabolism ; Receptors, G-Protein-Coupled/*metabolism; Animals ; Cell Line, Tumor ; Cell Membrane/metabolism ; Cells, Cultured ; Embryo, Mammalian/cytology ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Golgi Apparatus/metabolism ; HEK293 Cells ; Humans ; Mice, Inbred C57BL ; Microscopy, Confocal ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Signal Transduction ; Type C Phospholipases/metabolism
    • Abstract:
      Phospholipase C (PLC) enzymes hydrolyze the plasma membrane (PM) lipid phosphatidylinositol 4,5-bisphosphate (PI4,5P 2 ) to generate the second messengers inositol trisphosphate (IP 3 ) and diacylglycerol (DAG) in response to receptor activation in almost all mammalian cells. We previously found that stimulation of G protein-coupled receptors (GPCRs) in cardiac cells leads to the PLC-dependent hydrolysis of phosphatidylinositol 4-phosphate (PI4P) at the Golgi, a process required for the activation of nuclear protein kinase D (PKD) during cardiac hypertrophy. We hypothesized that GPCR-stimulated PLC activation leading to direct PI4P hydrolysis may be a general mechanism for DAG production. We measured GPCR activation-dependent changes in PM and Golgi PI4P pools in various cells using GFP-based detection of PI4P. Stimulation with various agonists caused a time-dependent reduction in PI4P-associated, but not PI4,5P 2 -associated, fluorescence at the Golgi and PM. Targeted depletion of PI4,5P 2 from the PM before GPCR stimulation had no effect on the depletion of PM or Golgi PI4P, total inositol phosphate (IP) production, or PKD activation. In contrast, acute depletion of PI4P specifically at the PM completely blocked the GPCR-dependent production of IPs and activation of PKD but did not change the abundance of PI4,5P 2 Acute depletion of Golgi PI4P had no effect on these processes. These data suggest that most of the PM PI4,5P 2 pool is not involved in GPCR-stimulated phosphoinositide hydrolysis and that PI4P at the PM is responsible for the bulk of receptor-stimulated phosphoinositide hydrolysis and DAG production.
      (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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    • Grant Information:
      R01 DE014756 United States DE NIDCR NIH HHS; R01 GM053536 United States GM NIGMS NIH HHS; R35 GM127303 United States GM NIGMS NIH HHS; R01 GM111735 United States GM NIGMS NIH HHS; R56 DE014756 United States DE NIDCR NIH HHS; R01 GM111997 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (Diglycerides)
      0 (Phosphatidylinositol Phosphates)
      0 (Phosphatidylinositols)
      0 (Receptors, G-Protein-Coupled)
      0 (phosphatidylinositol 4-phosphate)
      EC 3.1.4.- (Type C Phospholipases)
    • Publication Date:
      Date Created: 20180913 Date Completed: 20191009 Latest Revision: 20200309
    • Publication Date:
      20240829
    • Accession Number:
      PMC6413320
    • Accession Number:
      10.1126/scisignal.aan1210
    • Accession Number:
      30206135