Calcium in Red Blood Cells—A Perilous Balance

Ca2+ is a universal signalling molecule involved in regulating cell cycle and fate, metabolism and structural integrity, motility and volume. Like other cells, red blood cells (RBCs) rely on Ca2+ dependent signalling during differentiation from precursor cells. Intracellular Ca2+ levels in the circulating human RBCs take part not only in controlling biophysical properties such as membrane composition, volume and rheological properties, but also physiological parameters such as metabolic activity, redox state and cell clearance. Extremely low basal permeability of the human RBC membrane to Ca2+ and a powerful Ca2+ pump maintains intracellular free Ca2+ levels between 30 and 60 nM, whereas blood plasma Ca2+ is approximately 1.8 mM. Thus, activation of Ca2+ uptake has an impressive impact on multiple processes in the cells rendering Ca2+ a master regulator in RBCs. Malfunction of Ca2+ transporters in human RBCs leads to excessive accumulation of Ca2+ within the cells. This is associated with a number of pathological states including sickle cell disease, thalassemia, phosphofructokinase deficiency and other forms of hereditary anaemia. Continuous progress in unravelling the molecular nature of Ca2+ transport pathways allows harnessing Ca2+ uptake, avoiding premature RBC clearance and thrombotic complications. This review summarizes our current knowledge of Ca2+ signalling in RBCs emphasizing the importance of this inorganic cation in RBC function and survival.

[1]  Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn2+ and NR1 antagonist , 2008, Proceedings of the National Academy of Sciences.

[2]  V L Lew,et al.  Cytoplasmic calcium buffers in intact human red cells. , 1997, The Journal of physiology.

[3]  S. Chen,et al.  Regulation of the activity and phosphorylation of the plasma membrane Ca(2+)-ATPase by protein kinase C in intact human erythrocytes. , 1993, Archives of biochemistry and biophysics.

[4]  O. Potapova,et al.  The hSK4 (KCNN4) isoform is the Ca2+-activated K+ channel (Gardos channel) in human red blood cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  I. Bernhardt,et al.  Protein Kinase Cα and P-Type Ca2+ Channel CaV2.1 in Red Blood Cell Calcium Signalling , 2013, Cellular Physiology and Biochemistry.

[6]  F A Quiocho,et al.  Modulation of calmodulin plasticity in molecular recognition on the basis of x-ray structures. , 1993, Science.

[7]  S. Ochoa,et al.  Protein phosphorylation and translational control in reticulocytes: activation of the heme-controlled translational inhibitor by calcium ions and phospholipid. , 1985, Current topics in cellular regulation.

[8]  Kyung-Mi Joo,et al.  Procoagulant and prothrombotic activation of human erythrocytes by phosphatidic acid. , 2010, American journal of physiology. Heart and circulatory physiology.

[9]  J. Wiley Increased erythrocyte cation permeability in thalassemia and conditions of marrow stress. , 1981, The Journal of clinical investigation.

[10]  Simon J. Walker,et al.  NADPH oxidases in cardiovascular health and disease. , 2006, Antioxidants & redox signaling.

[11]  R. Hebbel,et al.  Oxidation of membrane thiols in sickle erythrocytes. , 1984, Progress in clinical and biological research.

[12]  N. Mohandas,et al.  Membrane remodeling during reticulocyte maturation. , 2010, Blood.

[13]  P. Romero,et al.  The role of calcium metabolism in human red blood cell ageing: a proposal. , 1999, Blood cells, molecules & diseases.

[14]  L. Kaestner Evaluation of human erythrocytes as model cells in photodynamic therapy. , 2003, General physiology and biophysics.

[15]  Oguz K. Baskurt,et al.  Red Blood Cell Aggregation , 2011 .

[16]  J. Hoffman,et al.  On the functional use of the membrane compartmentalized pool of ATP by the Na+ and Ca++ pumps in human red blood cell ghosts , 2009, The Journal of general physiology.

[17]  P. Lipp,et al.  Protein kinase C: the "masters" of calcium and lipid. , 2011, Cold Spring Harbor perspectives in biology.

[18]  Peter Lipp,et al.  Prostaglandin E2 activates channel-mediated calcium entry in human erythrocytes: an indication for a blood clot formation supporting process. , 2004, Thrombosis and haemostasis.

[19]  Lars Kaestner,et al.  Non-selective voltage-activated cation channel in the human red blood cell membrane. , 1999, Biochimica et biophysica acta.

[20]  E. Melloni,et al.  Ca2+-dependent neutral proteinase from human erythrocytes: activation by Ca2+ ions and substrate and regulation by the endogenous inhibitor. , 1984, Biochemistry international.

[21]  M. Pardela,et al.  Abnormal effect of sera from patients with atherosclerosis on calcium influx into normal erythrocytes. , 1992, Cor et vasa.

[22]  D. Vandorpe,et al.  Hypoxia Activates a Ca2+-Permeable Cation Conductance Sensitive to Carbon Monoxide and to GsMTx-4 in Human and Mouse Sickle Erythrocytes , 2010, PloS one.

[23]  V. Lew,et al.  Local Membrane Deformations Activate Ca2+-Dependent K+ and Anionic Currents in Intact Human Red Blood Cells , 2010, PloS one.

[24]  M. Gassmann,et al.  Functional NMDA receptors in rat erythrocytes. , 2010, American journal of physiology. Cell physiology.

[25]  A. G. Filoteo,et al.  Plasma Membrane Ca2+ ATPases as Dynamic Regulators of Cellular Calcium Handling , 2007, Annals of the New York Academy of Sciences.

[26]  T. Kaneko,et al.  Calcium-calmodulin dependent phosphorylation of erythrocyte pyruvate kinase. , 1982, Biochemical and biophysical research communications.

[27]  R. Kannagi,et al.  Evidence for membrane-associated calpain I in human erythrocytes. Detection by an immunoelectrophoretic blotting method using monospecific antibody. , 1984, Biochemistry.

[28]  R. Sprengel,et al.  Modulation of suicidal erythrocyte cation channels by an AMPA antagonist , 2009, Journal of cellular and molecular medicine.

[29]  S. Vetter,et al.  Phosphorylation of serine residues affects the conformation of the calmodulin binding domain of human protein 4.1. , 2001, European journal of biochemistry.

[30]  G. Gardos,et al.  The function of calcium in the potassium permeability of human erythrocytes. , 1958, Biochimica et biophysica acta.

[31]  L. Wolfe The red cell membrane and the storage lesion. , 1985, Clinics in haematology.

[32]  D. Steed,et al.  Alterations in Erythrocyte Rheology in Patients with Severe Peripheral Vascular Disease: 1. Cell Volume Dependence of Erythrocyte Rigidity , 1991, Angiology.

[33]  J. Falke,et al.  C2 domains of protein kinase C isoforms alpha, beta, and gamma: activation parameters and calcium stoichiometries of the membrane-bound state. , 2002, Biochemistry.

[34]  L. Kaestner Calcium signalling , 2012, Springer Berlin Heidelberg.

[35]  D Thomas,et al.  A comparison of fluorescent Ca2+ indicator properties and their use in measuring elementary and global Ca2+ signals. , 2000, Cell calcium.

[36]  M. Jiang,et al.  Deoxygenation-induced cation fluxes in sickle cells. IV. Modulation by external calcium. , 1995, The American journal of physiology.

[37]  Philip S Low,et al.  Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte membrane. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  G. Ronquist,et al.  The contribution of Ca+ calmodulin activation of human erythrocyte AMP deaminase (isoform E) to the erythrocyte metabolic dysregulation of familial phosphofructokinase deficiency. , 2006, Haematologica.

[39]  M. Magócsi,et al.  Signalling mechanisms in erythropoiesis: the enigmatic role of calcium. , 1997, Cellular signalling.

[40]  V. Lew,et al.  Calcium transport and ultrastructure of red cells in beta-thalassemia intermedia. , 1988, Blood.

[41]  T. Murakami,et al.  The cytosol of human erythrocytes contains a highly Ca2+-sensitive thiol protease (calpain I) and its specific inhibitor protein (calpastatin). , 1981, Journal of biochemistry.

[42]  N. Mohandas,et al.  Phosphorylation-dependent perturbations of the 4.1R-associated multiprotein complex of the erythrocyte membrane. , 2011, Biochemistry.

[43]  D. Barber,et al.  Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na(+)/H(+) exchanger isoform 1). , 2012, The Biochemical journal.

[44]  E. Kable,et al.  Ca2+ sensitivity of phospholipid scrambling in human red cell ghosts. , 1999, Cell calcium.

[45]  Joseph J. Falke,et al.  C2 Domains of Protein Kinase C Isoforms α, β, and γ: Activation Parameters and Calcium Stoichiometries of the Membrane-Bound State , 2002 .

[46]  J. Browning,et al.  The effect of deoxygenation on whole-cell conductance of red blood cells from healthy individuals and patients with sickle cell disease. , 2007, Blood.

[47]  C. Saldanha,et al.  Modulation of erythrocyte deformability by PKC activity. , 2008, Clinical hemorheology and microcirculation.

[48]  Yang Yang,et al.  Protein 4.1R-dependent multiprotein complex: New insights into the structural organization of the red blood cell membrane , 2008, Proceedings of the National Academy of Sciences.

[49]  N. Mohandas,et al.  Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. , 2013, Blood.

[50]  P. Sims,et al.  Isolation of an Erythrocyte Membrane Protein that Mediates Ca2+-dependent Transbilayer Movement of Phospholipid* , 1996, The Journal of Biological Chemistry.

[51]  H. Meiselman,et al.  Effects of calcium permeabilization on RBC rheologic behavior. , 1994, Biorheology.

[52]  V. Lew,et al.  Compartmentalization of sickle-cell calcium in endocytic inside-out vesicles , 1985, Nature.

[53]  F. Lang,et al.  TRPC6 Contributes to the Ca2+ Leak of Human Erythrocytes , 2008, Cellular Physiology and Biochemistry.

[54]  J. Vincent,et al.  Red blood cell rheology in sepsis , 2003, Intensive Care Medicine.

[55]  V. Lew,et al.  Stochastic nature and red cell population distribution of the sickling-induced Ca2+ permeability. , 1997, The Journal of clinical investigation.

[56]  D. Tillotson,et al.  Modulation of calcium channels in human erythroblasts by erythropoietin. , 1997, Blood.

[57]  R. Hebbel Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle erythrocytes with endothelium. , 1997, The Journal of clinical investigation.

[58]  P. Lipp,et al.  A system for optical high resolution screening of electrical excitable cells. , 2010, Cell calcium.

[59]  P. Christophersen,et al.  Evidence for a voltage-gated, non-selective cation channel in the human red cell membrane. , 1991, Biochimica et biophysica acta.

[60]  A. Means,et al.  Calmodulin: a prototypical calcium sensor. , 2000, Trends in cell biology.

[61]  S. Steinberg Structural basis of protein kinase C isoform function. , 2008, Physiological reviews.

[62]  P. Bennekou The voltage-gated non-selective cation channel from human red cells is sensitive to acetylcholine. , 1993, Biochimica et biophysica acta.

[63]  D. Nguyen,et al.  Lysophosphatidic acid induced red blood cell aggregation in vitro. , 2012, Bioelectrochemistry.

[64]  P. Low,et al.  Identification of cytoskeletal elements enclosing the ATP pools that fuel human red blood cell membrane cation pumps , 2012, Proceedings of the National Academy of Sciences.

[65]  R. Chaudhary,et al.  Oxidative injury as contributory factor for red cells storage lesion during twenty eight days of storage. , 2012, Blood transfusion = Trasfusione del sangue.

[66]  W. Schwarz,et al.  Properties of the CA2+-activated K+ conductance of human red cells as revealed by the patch-clamp technique. , 1983, Cell calcium.

[67]  M. Kelm,et al.  RBC NOS: regulatory mechanisms and therapeutic aspects. , 2008, Trends in molecular medicine.

[68]  T. Tiffert,et al.  Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells , 2007, Blood.

[69]  A. Newton,et al.  Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. , 2001, Chemical reviews.

[70]  M. Tanner,et al.  A band 3-based macrocomplex of integral and peripheral proteins in the RBC membrane. , 2003, Blood.

[71]  O. Baskurt,et al.  Shear stress activation of nitric oxide synthase and increased nitric oxide levels in human red blood cells. , 2011, Nitric oxide : biology and chemistry.

[72]  A. F. Rega,et al.  Phosphatidylcholine makes specific activity of the purified Ca(2+)-ATPase from plasma membranes independent of enzyme concentration. , 1999, Biochimica et biophysica acta.

[73]  G. Antonutto,et al.  Red blood cell senescence and neocytolysis in humans after high altitude acclimatization. , 2007, Blood cells, molecules & diseases.

[74]  Frederick Sachs,et al.  Piezo1: properties of a cation selective mechanical channel. , 2012, Channels.

[75]  B. Sarkadi,et al.  Transport parameters and stoichiometry of active calcium ion extrusion in intact human red cells. , 1977, Biochimica et biophysica acta.

[76]  J. Anagli,et al.  Ca(2+)-activated neutral protease is active in the erythrocyte membrane in its nonautolyzed 80-kDa form. , 1994, The Journal of biological chemistry.

[77]  D. E. Goll,et al.  The calpain system. , 2003, Physiological reviews.

[78]  J. Cheung,et al.  Mechanisms of Erythropoietin Signal Transduction: Involvement of Calcium Channels , 1994, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[79]  R. Beitner,et al.  Control of glycolytic enzymes through binding to cell structures and by glucose-1,6-bisphosphate under different conditions. The role of Ca2+ and calmodulin. , 1993, The International journal of biochemistry.

[80]  A. F. Rega,et al.  Activation of partial reactions of the Ca2+-ATPase from human red cells by Mg2+ and ATP. , 1978, Biochimica et biophysica acta.

[81]  P. Low,et al.  Phorbol ester stimulates a protein kinase C-mediated agatoxin-TK-sensitive calcium permeability pathway in human red blood cells. , 2002, Blood.

[82]  G. Debnath,et al.  Phosphatidylinositol-4,5-biphosphate (PIP2) differentially regulates the interaction of human erythrocyte protein 4.1 (4.1R) with membrane proteins. , 2006, Biochemistry.

[83]  T. Tiffert,et al.  Calcium Homeostasis in Normal and Abnormal Human Red Cells , 2003 .

[84]  M. Berridge,et al.  The versatility and universality of calcium signalling , 2000, Nature Reviews Molecular Cell Biology.

[85]  S. Schrier,et al.  Impaired erythrocyte calcium homeostasis in beta-thalassemia. , 1984, Blood.

[86]  P. Christophersen,et al.  The human red cell voltage-dependent cation channel. Part III: Distribution homogeneity and pH dependence. , 2006, Blood cells, molecules & diseases.

[87]  T. Tiffert,et al.  Elevated intracellular Ca2+ reveals a functional membrane nucleotide pool in intact human red blood cells , 2011, The Journal of general physiology.

[88]  C. Bergamini,et al.  Studies on tissue transglutaminases: interaction of erythrocyte type-2 transglutaminase with GTP. , 1993, The Biochemical journal.

[89]  T. Tiffert,et al.  Elevated intracellular Ca 2 + reveals a functional membrane nucleotide pool in intact human red blood cells , 2022 .

[90]  M. Molinari,et al.  Purification of μ-Calpain by a Novel Affinity Chromatography Approach. NEW INSIGHTS INTO THE MECHANISM OF THE INTERACTION OF THE PROTEASE WITH TARGETS (*) , 1995, The Journal of Biological Chemistry.

[91]  Y. Beuzard,et al.  Ca2+ permeability in deoxygenated sickle cells. , 1990, Blood.

[92]  L. Kaestner Cation Channels in Erythrocytes - Historical and Future Perspective , 2011 .

[93]  Lars Kaestner,et al.  Erythrocytes—the ‘house elves’ of photodynamic therapy , 2004, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[94]  O. Hamill Potassium and Chloride Channels in Red Blood Cells , 1983 .

[95]  P. Conlin,et al.  Protein kinase C and insulin regulation of red blood cell Na+/H+ exchange. , 1997, The American journal of physiology.

[96]  Y. Colin,et al.  Red blood cell phosphatidylserine exposure is responsible for increased erythrocyte adhesion to endothelium in central retinal vein occlusion , 2011, Journal of thrombosis and haemostasis : JTH.

[97]  C. Cooper,et al.  Nitric oxide synthases: structure, function and inhibition. , 2001, The Biochemical journal.

[98]  P. Christophersen,et al.  The Human Red Cell Voltage-regulated Cation Channel. The Interplay with the Chloride Conductance, the Ca2+-activated K+ Channel and the Ca2+ Pump , 2003, The Journal of Membrane Biology.

[99]  P. Low,et al.  Lysophosphatidic acid opens a Ca(++) channel in human erythrocytes. , 2000, Blood.

[100]  D. Spratt,et al.  Binding and activation of nitric oxide synthase isozymes by calmodulin EF hand pairs , 2006, The FEBS journal.

[101]  V. Lew,et al.  Progressive inhibition of the Ca pump and Ca : Ca exchange in sickle red cells , 1980, Nature.

[102]  P. Gane,et al.  Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin alpha5 chain and Lu/BCAM. , 2007, Blood.

[103]  J. Chung,et al.  Lysophosphatidic Acid Induces Thrombogenic Activity Through Phosphatidylserine Exposure and Procoagulant Microvesicle Generation in Human Erythrocytes , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[104]  J. García-Sancho,et al.  Calcium‐induced conversion of adenine nucleotides to inosine monophosphate in human red cells. , 1988, The Journal of physiology.

[105]  V. Fowler,et al.  A New Function for Adducin , 1996, The Journal of Biological Chemistry.

[106]  N. Mohandas,et al.  Altered phosphorylation of cytoskeleton proteins in sickle red blood cells: the role of protein kinase C, Rac GTPases, and reactive oxygen species. , 2010, Blood cells, molecules & diseases.

[107]  S. Zingde,et al.  Protein kinase C isoforms in human erythrocytes , 2001, Annals of Hematology.

[108]  F A Quiocho,et al.  Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin-peptide complex. , 1992, Science.

[109]  Peter Lipp,et al.  Cooking with Calcium: The Recipes for Composing Global Signals from Elementary Events , 1997, Cell.

[110]  Asya Makhro,et al.  Red cell investigations: art and artefacts. , 2013, Blood reviews.

[111]  J. Ellory,et al.  The conductance of red blood cells from sickle cell patients: ion selectivity and inhibitors , 2012, The Journal of physiology.

[112]  Gove Rb,et al.  Protein kinase C isoforms in human erythrocytes , 2001 .

[113]  G. Benaim,et al.  Ceramide and sphingosine have an antagonistic effect on the plasma-membrane Ca2+-ATPase from human erythrocytes. , 2002, The Biochemical journal.

[114]  T. Müller,et al.  Stimulation of human red blood cells leads to Ca2+-mediated intercellular adhesion. , 2011, Cell calcium.

[115]  Wonhwa Cho,et al.  Membrane-protein interactions in cell signaling and membrane trafficking. , 2005, Annual review of biophysics and biomolecular structure.

[116]  J. Hofrichter,et al.  Sickle cell hemoglobin polymerization. , 1990, Advances in protein chemistry.

[117]  Z. Eshhar,et al.  Calpain (Ca(2+)-dependent thiol protease) in erythrocytes of young and old individuals. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[118]  D. Granger,et al.  Critical role of endothelial cell-derived nitric oxide synthase in sickle cell disease-induced microvascular dysfunction. , 2006, Free radical biology & medicine.

[119]  Brian E. Smith,et al.  Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. , 2012, Blood.

[120]  M. Nakamura,et al.  A variety of calpain/calpastatin systems in mammalian erythrocytes. , 1993, Biochimica et biophysica acta.

[121]  C. Alfrey,et al.  The Negative Regulation of Red Cell Mass by Neocytolysis: Physiologic and Pathophysiologic Manifestations , 2005, Cellular Physiology and Biochemistry.

[122]  C. Ellis,et al.  Transfusion of stored red blood cells adhere in the rat microvasculature , 2009, Transfusion.

[123]  A. K. Solomon,et al.  Interaction between red cell membrane band 3 and cytosolic carbonic anhydrase , 1993, The Journal of Membrane Biology.

[124]  P. Sims,et al.  Molecular Cloning of Human Plasma Membrane Phospholipid Scramblase , 1997, The Journal of Biological Chemistry.

[125]  W. Groner,et al.  Cell Membrane and Volume Changes during Red Cell Development and Aging a , 1989, Annals of the New York Academy of Sciences.

[126]  H. Schatzmann Dependence on calcium concentration and stoichiometry of the calcium pump in human red cells , 1973, The Journal of physiology.

[127]  I. Bernhardt,et al.  Ion channels in the human red blood cell membrane: their further investigation and physiological relevance. , 2002, Bioelectrochemistry.

[128]  W. Wilbrandt A relation between the permeability of the red cell and its metabolism , 1937 .

[129]  T. Tiffert,et al.  Effects of deoxygenation on active and passive Ca2+ transport and on the cytoplasmic Ca2+ levels of sickle cell anemia red cells. , 1993, The Journal of clinical investigation.

[130]  B. Alvarez,et al.  Carbonic Anhydrase II Binds to and Enhances Activity of the Na+/H+ Exchanger* , 2002, The Journal of Biological Chemistry.

[131]  A. Chishti,et al.  Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology. , 2012, The Biochemical journal.

[132]  Philip S Low,et al.  Mapping of glycolytic enzyme-binding sites on human erythrocyte band 3. , 2006, The Biochemical journal.

[133]  P. Lipp,et al.  Morphologically Homogeneous Red Blood Cells Present a Heterogeneous Response to Hormonal Stimulation , 2013, PloS one.

[134]  H. Guizouarn,et al.  Multiple transport functions of a red blood cell anion exchanger, tAE1: its role in cell volume regulation , 2001, The Journal of physiology.

[135]  C. Borchgrevink,et al.  The Role of Red Cells in Haemostasis: the Relation between Haematocrit, Bleeding Time and Platelet Adhesiveness , 1961, British journal of haematology.

[136]  O. Olivieri,et al.  Deoxygenation affects tyrosine phosphoproteome of red cell membrane from patients with sickle cell disease. , 2010, Blood cells, molecules & diseases.

[137]  C. Chang,et al.  Changes of Red Blood Cell Surface Markers in a Blood Doping Model of Neocytolysis , 2009, Journal of Investigative Medicine.

[138]  M. Gassmann,et al.  N-methyl-D-aspartate receptors in human erythroid precursor cells and in circulating red blood cells contribute to the intracellular calcium regulation. , 2013, American journal of physiology. Cell physiology.

[139]  J. Eaton,et al.  Elevated Erythrocyte Calcium in Sickle Cell Disease , 1973, Nature.

[140]  S. Yedgar,et al.  RBC Adhesion to Vascular Endothelial Cells: More Potent than RBC Aggregation in Inducing Circulatory Disorders , 2008, Microcirculation.

[141]  Philip S Low,et al.  Characterization of the deoxyhemoglobin binding site on human erythrocyte band 3: implications for O2 regulation of erythrocyte properties. , 2008, Blood.

[142]  J. Elce,et al.  Immunogold Electron-Microscopic Localization of Calpain I in Human Erythrocytes , 1989, Thrombosis and Haemostasis.

[143]  M. R. Clark,et al.  Senescence of red blood cells: progress and problems. , 1988, Physiological reviews.

[144]  P. Devaux,et al.  Ion regulation of phosphatidylserine and phosphatidylethanolamine outside-inside translocation in human erythrocytes. , 1987, Biochimica et biophysica acta.

[145]  P Christophersen,et al.  The non-selective voltage-activated cation channel in the human red blood cell membrane: reconciliation between two conflicting reports and further characterisation. , 2000, Bioelectrochemistry.

[146]  Peter Lipp,et al.  Calcium imaging of individual erythrocytes: problems and approaches. , 2006, Cell calcium.

[147]  Alexander Barbul,et al.  Ca2+ promotes erythrocyte band 3 tyrosine phosphorylation via dissociation of phosphotyrosine phosphatase from band 3. , 2002, The Biochemical journal.

[148]  H. Jarrett,et al.  Human erythrocyte calmodulin. Further chemical characterization and the site of its interaction with the membrane. , 1979, The Journal of biological chemistry.

[149]  Athanassios D. Velentzas,et al.  Effects of pre-storage leukoreduction on stored red blood cells signaling: a time-course evaluation from shape to proteome. , 2012, Journal of proteomics.

[150]  S. Schrier,et al.  Red blood cell membrane abnormalities during storage: Correlation with in vivo survival , 1982, Transfusion.

[151]  W. W. Duke The Relation of Blood Platelets to Hemorrhagic Disease: Description of a Method for Determining the Bleeding Time and Coagulation Time and Report of Three Cases of Hemorrhagic Disease Relieved by Transfusion , 1910 .

[152]  Lutz Hu INNATE IMMUNE AND NON-IMMUNE MEDIATORS OF ERYTHROCYTE CLEARANCE , 2004 .

[153]  A. Chishti,et al.  Pharmacological inhibition of calpain‐1 prevents red cell dehydration and reduces Gardos channel activity in a mouse model of sickle cell disease , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[154]  S. N. Murthy,et al.  Transglutaminase-mediated remodeling of the human erythrocyte membrane skeleton: relevance for erythrocyte diseases with shortened cell lifespan. , 2011, Advances in enzymology and related areas of molecular biology.

[155]  K Konstantopoulos,et al.  Perspectives Series: Cell Adhesion in Vascular Biology Effects of Fluid Dynamic Forces on Vascular Cell Adhesion , 1996 .

[156]  T. Tiffert,et al.  Effects of deoxygenation on active and passive Ca2+ transport and cytoplasmic Ca2+ buffering in normal human red cells. , 1993, The Journal of physiology.

[157]  M. R. Clark,et al.  Permeability characteristics of deoxygenated sickle cells. , 1990, Blood.

[158]  Thomas Lauer,et al.  Red blood cells express a functional endothelial nitric oxide synthase. , 2006, Blood.

[159]  H. Lutz Innate immune and non-immune mediators of erythrocyte clearance. , 2004, Cellular and molecular biology.

[160]  G. Bosman,et al.  Erythrocyte Aging: A More than Superficial Resemblance to Apoptosis? , 2005, Cellular Physiology and Biochemistry.

[161]  P. Low,et al.  Role of red blood cells in thrombosis. , 1999, Current opinion in hematology.

[162]  H. Barrabin,et al.  Mechanism of modulation of the plasma membrane Ca(2+)-ATPase by arachidonic acid. , 2008, Prostaglandins & other lipid mediators.

[163]  R. Campbell,et al.  Structure-function relationships in calpains. , 2012, The Biochemical journal.

[164]  R. Novak,et al.  Dynamic changes in the distribution of the calcium-activated neutral protease in human red blood cells following cellular insult and altered Ca2+ homeostasis. , 1992, Toxicology and applied pharmacology.

[165]  S. Kidokoro,et al.  Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase , 2012, Biochemical Journal.

[166]  E. Melloni,et al.  Site-directed activation of calpain is promoted by a membrane-associated natural activator protein. , 1993, Biochemical Journal.

[167]  D. Nguyen,et al.  Regulation of Phosphatidylserine Exposure in Red Blood Cells , 2011, Cellular Physiology and Biochemistry.

[168]  P. Christophersen,et al.  Pharmacology of the human red cell voltage-dependent cation channel; Part I. Activation by clotrimazole and analogues. , 2004, Blood cells, molecules & diseases.

[169]  P. Gascard,et al.  Effect of complete protein 4.1R deficiency on ion transport properties of murine erythrocytes. , 2006, American journal of physiology. Cell physiology.

[170]  B. Roelofsen,et al.  The asymmetric distribution of phospholipids in the human red cell membrane. A combined study using phospholipases and freeze-etch electron microscopy. , 1973, Biochimica et biophysica acta.

[171]  N. Mohandas,et al.  Modulation of Erythrocyte Membrane Mechanical Function by Protein 4.1 Phosphorylation* , 2005, Journal of Biological Chemistry.

[172]  V. Lew,et al.  Calcium accumulated by sickle cell anemia red cells does not affect their potassium (86Rb+) flux components. , 1986, Blood.

[173]  M. Gassmann,et al.  Erythropoietin activates nitric oxide synthase in murine erythrocytes. , 2009, American journal of physiology. Cell physiology.

[174]  N. Mohandas,et al.  Red cell membrane: past, present, and future. , 2008, Blood.

[175]  Trese Leinders-Zufall,et al.  Single Ca(2+)-activated K+ channels in human erythrocytes: Ca2+ dependence of opening frequency but not of open lifetimes. , 1992, Biochimica et biophysica acta.

[176]  D. Clapham,et al.  Calcium signaling , 1995, Cell.

[177]  Mitsuhiko Ikura,et al.  Calmodulin in Action Diversity in Target Recognition and Activation Mechanisms , 2002, Cell.

[178]  A. De Simoni,et al.  The voltage-dependent nonselective cation current in human red blood cells studied by means of whole-cell and nystatin-perforated patch-clamp techniques. , 2004, Biochimica et biophysica acta.

[179]  M. Mann,et al.  In-depth analysis of the membrane and cytosolic proteome of red blood cells. , 2006, Blood.

[180]  P. Devaux,et al.  Aminophospholipid translocase of human erythrocytes: phospholipid substrate specificity and effect of cholesterol. , 1989, Biochemistry.

[181]  P. Gascard,et al.  Regulation and post-translational modification of erythrocyte membrane and membrane-skeletal proteins. , 1992, Seminars in hematology.

[182]  P. Romero,et al.  Differences in Ca2+ pumping activity between sub-populations of human red cells. , 1997, Cell calcium.

[183]  P. Sims,et al.  Change in conformation of plasma membrane phospholipid scramblase induced by occupancy of its Ca2+ binding site. , 1998, Biochemistry.