Erythropoietin receptor-operated Ca2+ channels: Activation by phospholipase C-γ1

Mario B. Marrero, Richard C. Venema, Heping Ma, Brian N. Ling, Douglas C. Eaton

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Erythropoietin (EPO) increases Ca2+ influx in vascular smooth muscle cells and acts both as a direct vasoconstrictor and vascular growth factor (that is, angiogenesis). However, the mechanism by which EPO promotes extracellular Ca2+ entry in contractile cells has not been elucidated. In hematopoietic cells, EPO induces tyrosine kinase (TK)-dependent activation of phospholipase C (PLC)-γ1 and Ca2+ influx via a voltage-independent Ca2+ conductance. In contractile mesangial cells, we have recently characterized a voltage-independent, 1 pS Ca2+ channel that is dependent on both TK and PLC-γ1 activity. Therefore, we examined cultured rat glomerular mesangial cells after timed exposure to recombinant human EPO (20 U/ml). Erythropoietin increased the tyrosine phosphorylation of PLC-γ1, promoted membrane complex formation between PLC-γ1 and the EPO receptor itself, and raised the levels of intracellular inositol 1,4,5-trisphosphate and intracellular Ca2+. Consistent with our previous studies, 1 pS Ca2+ channel activity was extremely low under basal, unstimulated conditions in cell-attached patches, but was dramatically increased when EPO was present in the patch pipette. Tyrosine kinase inhibition with 100 μM genistein or 1 μM PP1 (Src; selective tyrosine kinase inhibitor) prevented all of these EPO-induced responses. We conclude that: (1) EPO-induced stimulation of l pS Ca2+ channels is mediated via a cytosolic Src TK in glomerular mesangial cells. (2) Stimulation of this Ca2+-activated, Ca2+-permeable channel is dependent on the tyrosine phosphorylation/activation of PLC-γ1. (3) This cascade provides a possible mechanism for the vasoconstriction and hypertension observed with clinical EPO use for the treatment of chronic anemias.

Original languageEnglish (US)
Pages (from-to)1259-1268
Number of pages10
JournalKidney International
Volume53
Issue number5
DOIs
StatePublished - Jan 1 1998

Keywords

  • Anemia
  • Hypertension
  • Intracellular Ca
  • Renal failure
  • Tyrosine kinase

ASJC Scopus subject areas

  • Nephrology

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