Phosphatidylinositol 3-kinase-mediated endocytosis of renal Na+,K+- ATPase α subunit in response to dopamine

Alexander V. Chibalin, Juleen R. Zierath, Adrian I. Katz, Per Olof Berggren, Alejandro M. Bertorello

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Dopamine (DA) inhibition of Na+,K+-ATPase in proximal tubule cells is associated with increased endocytosis of its α and β subunits into early and late endosomes via a clathrin vesicle-dependent pathway. In this report we evaluated intracellular signals that could trigger this mechanism, specifically the role of phosphatidylinositol 3-kinase (PI 3-K), the activation of which initiates vesicular trafficking and targeting of proteins to specific cell compartments. DA stimulated PI 3-K activity in a time- and dose-dependent manner, and this effect was markedly blunted by wortmannin and LY 294002. Endocytosis of the Na+,K+-ATPase α subunit in response to DA was also inhibited in dose-dependent manner by wortmannin and LY 294002. Activation of PI 3-K generally occurs by association with tyrosine kinase receptors. However, in this study immunoprecipitation with a phosphotyrosine antibody did not reveal PI 3-K activity. DA-stimulated endocytosis of Na+,K+-ATPase α subunits required protein kinase C, and the ability of DA to stimulate PI 3-K was blocked by specific protein kinase C inhibitors. Activation of PI 3-K is mediated via the D1 receptor subtype and the sequential activation of phospholipase A2, arachidonic acid, and protein kinase C. The results indicate a key role for activation of PI 3-K in the endocytic sequence that leads to internalization of Na+,K+-ATPase α subunits in response to DA, and suggest a mechanism for the participation of protein kinase C in this process.

Original languageEnglish (US)
Pages (from-to)1209-1220
Number of pages12
JournalMolecular biology of the cell
Volume9
Issue number5
DOIs
StatePublished - May 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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