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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Erythropoietin receptor-operated Ca2+ channels: activation by phospholipase C-gamma 1.

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)-gamma 1 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-gamma 1 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-gamma 1, promoted membrane complex formation between PLC-gamma 1 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 micron genistein or 1 micron PP1 ( Src; selective tyrosine kinase inhibitor) prevented all of these EPO-induced responses. We conclude that: (1) EPO- induced stimulation of 1 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-gamma 1. (3) This cascade provides a possible mechanism for the vasoconstriction and hypertension observed with clinical EPO use for the treatment of chronic anemias.[1]

References

  1. Erythropoietin receptor-operated Ca2+ channels: activation by phospholipase C-gamma 1. Marrero, M.B., Venema, R.C., Ma, H., Ling, B.N., Eaton, D.C. Kidney Int. (1998) [Pubmed]
 
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