Intracellular endothelin type B receptor-driven Ca2+ signal elicits nitric oxide production in endothelial cells

Elena Deliu, G. Cristina Brailoiu, Karthik Mallilankaraman, Hong Wang, Muniswamy Madesh, Ashiwel S. Undieh, Walter J. Koch, Eugen Brailoiu

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Endothelin-1 exerts its actions via activation of ETA and ETBGq/11 protein-coupled receptors, located in the plasmalemma, cytoplasm, and nucleus. Although the autocrine/paracrine nature of endothelin-1 signaling has been extensively studied, its intracrine role has been largely attributed to interaction with receptors located on nuclear membranes and the nucleoplasm. Because ETB receptors have been shown to be targeted to endolysosomes, we used intracellular microinjection and concurrent imaging methods to test their involvement in Ca2+ signaling and subsequential NO production. We provide evidence that microinjected endothelin-1 produces a dose-dependent elevation in cytosolic calcium concentration in ETB-transfected cells and endothelial cells; this response is sensitive to ETB but not ETA receptor blockade. In endothelial cells, the endothelin-1-induced Ca2+ response is abolished upon endolysosomal but not Golgi disruption. Moreover, the effect is prevented by inhibition of microautophagy and is sensitive to inhibitors of the phospholipase C and inositol 1,4,5-trisphosphate receptor. Furthermore, intracellular endothelin-1 increases nitric oxide via an ET B-dependent mechanism. Our results indicate for the first time that intracellular endothelin-1 activates endolysosomal ETB receptors and increase cytosolic Ca2+ and nitric oxide production. Endothelin-1 acts in an intracrine fashion on endolysosomal ETB to induce nitric oxide formation, thus modulating endothelial function.

Original languageEnglish (US)
Pages (from-to)41023-41031
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number49
DOIs
StatePublished - Nov 30 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Deliu, E., Brailoiu, G. C., Mallilankaraman, K., Wang, H., Madesh, M., Undieh, A. S., Koch, W. J., & Brailoiu, E. (2012). Intracellular endothelin type B receptor-driven Ca2+ signal elicits nitric oxide production in endothelial cells. Journal of Biological Chemistry, 287(49), 41023-41031. https://doi.org/10.1074/jbc.M112.418533