title: Functional plasticity of the N-methyl-d-aspartate receptor in differentiating human erythroid precursor cells.
abstract: Calcium signaling is essential to support erythroid proliferation and differentiation. Precise control of the intracellular Ca(2+) levels in erythroid precursor cells (EPCs) is afforded by coordinated expression and function of several cation channels, including the recently identified N-methyl-d-aspartate receptor (NMDAR). Here, we characterized the changes in Ca(2+) uptake and electric currents mediated by the NMDARs occurring during EPC differentiation using flow cytometry and patch clamp. During erythropoietic maturation, subunit composition and properties of the receptor changed; in proerythroblasts and basophilic erythroblasts, fast deactivating currents with high amplitudes were mediated by the GluN2A subunit-dominated receptors, while at the polychromatic and orthochromatic erythroblast stages, the GluN2C subunit was getting more abundant, overriding the expression of GluN2A. At these stages, the currents mediated by the NMDARs carried the features characteristic of the GluN2C-containing receptors, such as prolonged decay time and lower conductance. Kinetics of this switch in NMDAR properties and abundance varied markedly from donor to donor. Despite this variability, NMDARs were essential for survival of EPCs in any subject tested. Our findings indicate that NMDARs have a dual role during erythropoiesis, supporting survival of polychromatic erythroblasts and contributing to the Ca(2+) homeostasis from the orthochromatic erythroblast stage to circulating red blood cells.
authors: Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland; Division of Hematology University Hospital Zurich, Zurich, Switzerland; University Children's Hospital, Zurich, Switzerland;
authors: Pascal
authors: P
authors: Hänggi
authors: Division of Pathophysiology and Repair, School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors: Vsevolod
authors: V
authors: Telezhkin
authors: Division of Pathophysiology and Repair, School of Biosciences, Cardiff University, Cardiff, United Kingdom;
authors: Paul J
authors: PJ
authors: Kemp
authors: University Children's Hospital, Zurich, Switzerland; Children's Research Center, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Markus
authors: M
authors: Schmugge
authors: Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Max
authors: M
authors: Gassmann
authors: Division of Hematology University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Jeroen S
authors: JS
authors: Goede
authors: University Children's Hospital, Zurich, Switzerland; Children's Research Center, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors: Oliver
authors: O
authors: Speer
authors: Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland annab@access.uzh.ch.
authors: Anna
authors: A
authors: Bogdanova
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D016202:N-Methylaspartate / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D002118:Calcium; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005998:Glycine; D016202:N-Methylaspartate; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C432823:NR2C NMDA receptor
keywords: NMDA receptor; calcium; differentiation; erythropoiesis