Does Erythropoietin Regulate TRPC Channels in Red Blood Cells?

Abstract

Background: Cation channels play an essential role in red blood cells (RBCs) ion homeostasis. One set of ion channels are the transient receptor potential channels of canonical type (TRPC channels). The abundance of these channels in primary erythroblasts, erythroid cell lines and RBCs was associated with an increase in intracellular Ca 2+ upon stimulation with Erythropoietin (Epo). In contrast two independent studies on Epo-treated patients revealed diminished basal Ca 2+ concentration or reduced phosphatidylserine exposure to the outer membrane leaflet. Methods: To resolve the seemingly conflicting reports we challenged mature human and mouse RBCs of several genotypes with Epo and Prostaglandin E 2 (PGE 2 ) and recorded the intracellular Ca 2+ content. Next Generation Sequencing was utilised to approach a molecular analysis of reticulocytes. Results/Conclusions: Our results allow concluding that Epo and PGE 2 regulation of the Ca 2+ homeostasis is distinctly different between murine and human RBCs and that changes in intracellular Ca 2+ upon Epo treatment is a primary rather than a compensatory effect. In human RBCs, Epo itself has no effect on Ca 2+ fluxes but inhibits the PGE 2 -induced Ca 2+ entry. In murine mature RBCs functional evidence indicates TRPC4/C5 mediated Ca 2+ entry activated by Epo whereas PGE 2 leads to a TRPC independent Ca 2+ entry.