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Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages

Author

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  • Johnathan Canton

    (Program in Cell Biology, Hospital for Sick Children)

  • Daniel Schlam

    (Program in Cell Biology, Hospital for Sick Children)

  • Christian Breuer

    (Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn)

  • Michael Gütschow

    (Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn)

  • Michael Glogauer

    (Faculty of Dentistry, University of Toronto)

  • Sergio Grinstein

    (Program in Cell Biology, Hospital for Sick Children
    Keenan Research Centre of the Li Ka Shing Knowledge Institute)

Abstract

Macropinocytosis can be induced in several cell types by stimulation with growth factors. In selected cell types, notably macrophages and dendritic cells, macropinocytosis occurs constitutively, supporting the uptake of antigens for subsequent presentation. Despite their different mode of initiation and contrasting physiological roles, it is tacitly assumed that both types of macropinocytosis are mechanistically identical. We report that constitutive macropinocytosis is stringently calcium dependent, while stimulus-induced macropinocytosis is not. Extracellular calcium is sensed by G-protein-coupled calcium-sensing receptors (CaSR) that signal macropinocytosis through Gα-, phosphatidylinositol 3-kinase and phospholipase C. These pathways promote the recruitment of exchange factors that stimulate Rac and/or Cdc42, driving actin-dependent formation of ruffles and macropinosomes. In addition, the heterologous expression of CaSR in HEK293 cells confers on them the ability to perform constitutive macropinocytosis. Finally, we show that CaSR-induced constitutive macropinocytosis facilitates the sentinel function of macrophages, promoting the efficient delivery of ligands to cytosolic pattern-recognition receptors.

Suggested Citation

  • Johnathan Canton & Daniel Schlam & Christian Breuer & Michael Gütschow & Michael Glogauer & Sergio Grinstein, 2016. "Calcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11284
    DOI: 10.1038/ncomms11284
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    Cited by:

    1. Eunnyung Bae & Ping Huang & Gaёlle Müller-Greven & Dolores Hambardzumyan & Andrew Edward Sloan & Amy S. Nowacki & Nicholas Marko & Cathleen R. Carlin & Candece L. Gladson, 2022. "Integrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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