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Molecular Pharmacology

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Research ArticleArticle

Inhibitors of PI(4,5)P2 Synthesis Reveal Dynamic Regulation of IgE Receptor Signaling by Phosphoinositides in RBL Mast Cells

Marcela de Souza Santos, Rose Mary Zumstein Georgetto Naal, Barbara Baird and David Holowka
Molecular Pharmacology April 2013, 83 (4) 793-804; DOI: https://doi.org/10.1124/mol.112.082834
Marcela de Souza Santos
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil (M.S.S., R.M.Z.G.N.); Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York (B.B., D.H.)
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Rose Mary Zumstein Georgetto Naal
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil (M.S.S., R.M.Z.G.N.); Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York (B.B., D.H.)
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Barbara Baird
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil (M.S.S., R.M.Z.G.N.); Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York (B.B., D.H.)
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David Holowka
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil (M.S.S., R.M.Z.G.N.); Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York (B.B., D.H.)
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Abstract

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a versatile phospholipid that participates in many membrane-associated signaling processes. PI(4,5)P2 production at the plasma membrane (PM) depends on levels of its precursor, phosphatidylinositol 4-phosphate (PI4P), synthesized principally by two intracellular enzymes, PI4-kinases IIIα and IIIb; the former is preferentially inhibited by phenylarsine oxide (PAO). We found that PAO and quercetin, another lipid kinase inhibitor, rapidly inhibit Ca2+ responses to antigen in IgE-sensitized rat basophilic leukemia mast cells. Quercetin also rapidly inhibits store-operated Ca2+ influx stimulated by thapsigargin. In addition, quercetin and PAO effectively inhibit antigen-stimulated ruffling and spreading in these cells, and they inhibit endocytosis of crosslinked IgE receptor complexes, evidently by inhibiting pinching off of endocytic vesicles containing the clustered IgE receptors. A minimal model to account for these diverse effects is inhibition of PI(4,5)P2 synthesis by PAO and quercetin. To characterize the direct effects of these agents on PI(4,5)P2 synthesis, we monitored the reappearance of the PI(4,5)P2-specific PH domain PH-phospholipase C δ-EGFP at the PM after Ca2+ ionophore (A23187)-induced PI(4,5)P2 hydrolysis, followed by Ca2+ chelation with excess EGTA. Resynthesized PI(4,5)P2 initially appears as micron-sized patches near the PM. Addition of quercetin subsequent to A23187-induced PI(4,5)P2 hydrolysis reduces PI(4,5)P2 resynthesis in PM-associated patches, and PAO reduces PI(4,5)P2 at the PM while enhancing PI(4,5)P2 accumulation at the Golgi complex. Taken together, these results provide evidence that PI4P generated by PI4-kinase IIIα is dynamically coupled to PI(4,5)P2 pools at the PM that are important for downstream signaling processes activated by IgE receptors.

Footnotes

  • This work was supported by the Brazilian foundations CAPES-Coordenação de Aperfeiçoamento de Pessoal de Nível Superior [Grant 1277/10-3] and FAPESP-Fundação de Amparo à Pesquisa do Estado de São Paulo [Grant 2008/01712-6]; and by the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R01AI022449].

  • This work was previously presented as part of a thesis: de Souza Santos M. (2012) Study of IgE-mediated mast cell signaling: development of inhibitors and effect of reduced levels of phosphatidylinositol 4,5-bisphosphate. Doctoral thesis, Ribeirão Preto, São Paulo, Brazil.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • dx.doi.org/10.1124/mol.112.082834.

  • Received October 8, 2012.
  • Accepted January 11, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (4)
Molecular Pharmacology
Vol. 83, Issue 4
1 Apr 2013
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Research ArticleArticle

PI(4,5)P2 Synthesis in IgE Receptor Signaling

Marcela de Souza Santos, Rose Mary Zumstein Georgetto Naal, Barbara Baird and David Holowka
Molecular Pharmacology April 1, 2013, 83 (4) 793-804; DOI: https://doi.org/10.1124/mol.112.082834

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Research ArticleArticle

PI(4,5)P2 Synthesis in IgE Receptor Signaling

Marcela de Souza Santos, Rose Mary Zumstein Georgetto Naal, Barbara Baird and David Holowka
Molecular Pharmacology April 1, 2013, 83 (4) 793-804; DOI: https://doi.org/10.1124/mol.112.082834
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