Erythropoietin stimulates a rise in intracellular-free calcium concentration in single BFU-E derived erythroblasts at specific stages of differentiation

Miller, BA; Cheung, JY; Tillotson, DL; Hope, SM; Scaduto, RC Jr

doi:10.1182/blood.v73.5.1188.bloodjournal7351188

Cited by 4 publications

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“…The assembly and performance characteristics of our digital imaging system for the study of events occurring in a single cell have been extensively described previously (5,15,25) . Briefly, the system consists of a SPEX dual wavelengths fluorimeter (SPEX Industries, Edison, NJ), a Zeiss IM 35 inverted microscope, and an intensified charge-coupled device (CCD) video camera (model 3000 F ; Fairchild, Sunnyvale, CA) .…”

Section: Digital Imaging Systemmentioning

confidence: 99%

“…where Kd is the apparent dissociation constant for Ca2+ (224 nM for fura-2) (9), R is the 350/380 ratio of fluorescence, R,in and R. are the R values when intracellular fura-2 was clamped with ionomycin (2 AM) at zero Ca 2+ (4 mM EGTA) and 4 mM Ca2+ (5,15), respectively, and Sf2/Sb2 is…”

Section: R -Rmin Sf2mentioning

confidence: 99%

“…Thus, calcium transients occurring in different cells at different times might have been averaged to undetectability as previously postulated by Kruskal and Maxfield (12). To overcome these difficulties, we used our previously described digital video imaging system (5,15,25) to simultaneously measure phagocytic events and [Ca2 +]i in…”

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confidence: 99%

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Calcium transients during Fc receptor-mediated and nonspecific phagocytosis by murine peritoneal macrophages.

Hishikawa

Cheung

Yelamarty

et al. 1991

The Journal of Cell Biology

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Abstract. Studies with populations of macrophages have produced conflicting results concerning the possibility that the concentration of intracellular ionized calcium ([Ca2+]i) may act as an important mediator for phagocytosis. Since asynchronous changes in [Ca"] i in individual cells undergoing phagocytosis may be averaged to undetectability in population studies, we studied single adhering murine macrophages using fura-2 and our previously described digital imaging system . The proportion of macrophages phagocytosing IgG-coated latex beads was greater than for uncoated beads (percent phagocytosing cells: 71 f 7 vs. 27 t 7, P < 0.01) . Phagocytosis of IgG-coated and uncoated beads was always associated with a calcium transient that preceded the initiation of phagocytosis . No calcium transients were detected in cells that bound but did not phagocytose beads . Four major differences between Fc receptor-mediated and nonspecific phagocytosis were detected : (a) the duration of calcium transients was longer for nonspecific phagocytosis compared with Fc B NDING and endocytosis of immune complexes by macrophages are mainly mediated by membrane receptors for the Fc portion of IgG (Fc receptors) (20) . Transmembrane signaling for the initiation of phagocytosis of bound immune complexes is not currently understood. Since calcium regulates the assembly and disassembly of cytoskeletal elements (7,18,22), it has long been proposed that a transient increase in the concentration of intracellular ionized calcium ([Ca2+]i) acts as a second messenger for phagocytosis . However, available studies with populations of macrophages have shown conflicting results concerning this possibility (8,14,26) . Studies of cell populations in which no calcium transients were observed may have been hampered by the fact that phagocytosis is an asynchronous event in different cells (14). Thus, calcium transients occurring in different cells at different times might have been averaged to undetectability as previously postulated by Kruskal and Maxfield (12). To overcome these difficulties, we used our previously described digital video imaging system (5,15,25) receptor-mediated phagocytosis (69.9 f 10.2 vs. 48.7 f 4 .7 s, P < 0.05) and the magnitude of calcium transients was less for nonspecific phagocytosis (178 f 43 vs. 349 t 53 nM, P < 0.05); (b) removal of extracellular calcium abolished the calcium transients associated with nonspecific phagocytosis but had no effect on those associated with receptor-mediated phagocytosis; (c) in the absence of extracellular calcium, buffering intracellular calcium with a chelator reduced Fc receptor-mediated phagocytosis but had no additive inhibitory effect on nonspecific phagocytosis ; and (d) inhibition of protein kinase C (PKC) with staurosporine inhibited nonspecific phagocytosis but had no effect on receptor-mediated phagocytosis. Our observations suggest that despite both types of phagocytosis being associated with intracellular calcium transients, the role played by intracellular calcium in the sign...

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Section: Digital Imaging Systemmentioning

confidence: 99%

Section: R -Rmin Sf2mentioning

confidence: 99%

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Calcium transients during Fc receptor-mediated and nonspecific phagocytosis by murine peritoneal macrophages.

Hishikawa

Cheung

Yelamarty

et al. 1991

The Journal of Cell Biology

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“…TRPC proteins mediate Ca 2+ influx into erythroid progenitors (Tong et al, 2004;Tong et al, 2008). It has been demonstrated that regulation of intracellular Ca 2+ by EPO plays a critical role in the survival, proliferation, and differentiation of erythroid progenitors (Hensold et al, 1991;Miller et al, 1989). Among the six members of the mouse TRPC family, TRPC2 and TRPC6 mRNAs and proteins are expressed in erythropoietic cell lines (Tong et al, 2004;Tong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

DOT1L methyltransferase regulates the calcium influx in erythroid progenitor cells in response to erythropoietin

Feng

Borosha

Ratri

et al. 2020

Preprint

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Erythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of hematopoietic progenitor cells. An important downstream response of EPO signaling is calcium influx, which is regulated by transient receptor potential channel (TRPC) proteins, particularly TRPC2 and TRPC6. While EPO induces Ca2+influx through TRPC2, TRPC6 inhibits the function of TRPC2. Thus, interactions between TRPC2 and TRPC6 regulate the rate of Ca2+influx in EPO-induced erythropoiesis. In this study, we observed that the expression of TRPC6 in c-KIT positive erythroid progenitor cells is regulated by DOT1L. DOT1L is a methyltransferase that plays an important role in many biological processes during embryonic development, including early erythropoiesis. We previously reported that Dot1L knockout (Dot1L-KO) hematopoietic progenitors in the yolk sac failed to develop properly, which resulted in lethal anemia. In this study, we have detected a marked downregulation of Trpc6 gene expression in Dot1L-KO progenitor cells in the yolk sac compared to wildtype. However, the expression of Trpc2, the positive regulator of Ca2+influx, remained unchanged. The promoter and the proximal region of the Trpc6 gene loci exhibited an enrichment of H3K79 methylation, which is mediated solely by DOT1L. As the loss of DOT1L affects the expression of TRPC6, which inhibits Ca2+influx by TRPC2, Dot1L-KO progenitor cells in the yolk sac exhibit accelerated and sustained high levels of Ca2+influx. Such heightened Ca2+ levels might have detrimental effects on the development of hematopoietic progenitor cells in response to erythropoietin.

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“…Novel signaling pathways of erythropoietin may be identified by studying the mechanisms regulating TRPC channels activation, membrane expression, and physiological function in erythroid cells. This may further lead to new approaches for therapeutic intervention in diseases involving abnormal erythropoiesis . Moreover, a recent analysis in red blood cells confirmed a direct correlation between the intracellular concentration of free Ca 2+ and the hemoglobin oxygen saturation …”

Section: Cascade Events Triggered By Erythropoietin In the Bone Marromentioning

confidence: 84%

Erythropoiesis and chronic kidney disease–related anemia: From physiology to new therapeutic advancements

Cernaro

Coppolino

Visconti

et al. 2018

Medicinal Research Reviews

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Erythropoiesis is triggered by hypoxia and is strictly regulated by hormones, growth factors, cytokines, and vitamins to ensure an adequate oxygen delivery to all body cells. Abnormalities in one or more of these factors may induce different kinds of anemia requiring different treatments. A key player in red blood cell production is erythropoietin. It is a glycoprotein hormone, mainly produced by the kidneys, that promotes erythroid progenitor cell survival and differentiation in the bone marrow and regulates iron metabolism. A deficit in erythropoietin synthesis is the main cause of the normochromic normocytic anemia frequently observed in patients with progressive chronic kidney disease. The present review summarizes the most recent findings about each step of the erythropoietic process, going from the renal oxygen sensing system to the cascade of events induced by erythropoietin through its own receptor in the bone marrow. The paper also describes the new class of drugs designed to stabilize the hypoxia-inducible factor by inhibiting prolyl hydroxylase, with a discussion about their metabolism, disposition, efficacy, and safety. According to many trials, these drugs seem able to simulate tissue hypoxia and then stimulate erythropoiesis in patients affected by renal impairment. In conclusion, the in-depth investigation of all events involved in erythropoiesis is crucial to understand anemia pathophysiology and to identify new therapeutic strategies, in an attempt to overcome the potential side effects of the commonly used erythropoiesis-stimulating agents.

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Erythropoietin stimulates a rise in intracellular-free calcium concentration in single BFU-E derived erythroblasts at specific stages of differentiation

Cited by 4 publications

References 0 publications

Calcium transients during Fc receptor-mediated and nonspecific phagocytosis by murine peritoneal macrophages.

Calcium transients during Fc receptor-mediated and nonspecific phagocytosis by murine peritoneal macrophages.

DOT1L methyltransferase regulates the calcium influx in erythroid progenitor cells in response to erythropoietin

Erythropoiesis and chronic kidney disease–related anemia: From physiology to new therapeutic advancements

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