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9 - The Erythrocyte Membrane

from SECTION TWO - PATHOPHYSIOLOGY OF HEMOGLOBIN AND ITS DISORDERS

Published online by Cambridge University Press:  03 May 2010

Martin H. Steinberg ,
Bernard G. Forget ,
Douglas R. Higgs  and
David J. Weatherall
By
Patrick G. Gallagher  and
Clinton H. Joiner
Martin H. Steinberg
Affiliation:
Boston University
Bernard G. Forget
Affiliation:
Yale University, Connecticut
Douglas R. Higgs
Affiliation:
MRC Institute of Molecular Medicine, University of Oxford
David J. Weatherall
Affiliation:
Albert Einstein College of Medicine, New York
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Summary

INTRODUCTION

Hemoglobinopathies, including the thalassemia syndromes and sickle cell disease, are complex disorders with protean manifestations. Their pathophysiology is influenced by environmental and genetic factors in addition to the pleiotropic effects of the globin gene mutations themselves. The erythrocyte membrane plays a critical role in these disorders because of the effects of its structural and functional perturbations and alterations in ion and water homeostasis regulated by membrane proteins. The first portion of this chapter reviews the structural and functional characteristics of the erythrocyte membrane; this is followed by a review of the alterations in ion and water homeostasis observed in the erythrocytes of sickle cell disease and thalassemia.

MEMBRANE STRUCTURE AND FUNCTION

The erythrocyte membrane is a complex, multifunctional structure. Although providing a protective layer between hemoglobin and other intracellular components and the external environment, it provides the erythrocyte with the deformability and stability required to withstand its travels through the circulation. The erythrocyte is subjected to high sheer stress in the arterial system, dramatic changes in size in the microcirculation, and wide variations in tonicity, pH, and pO2 as it travels throughout the body. It facilitates the transport of cations, anions, urea, water and other small molecules in and out of the cell, but denies entry to larger molecules, particularly if charged. A unique anucleate cell, the erythrocyte has a limited capacity for self-repair.

Membrane Structure

The erythrocyte membrane is composed of a lipid bilayer linked to an underlying cortical membrane skeleton.

Information

Type
Chapter
Information
Disorders of Hemoglobin
Genetics, Pathophysiology, and Clinical Management
 , pp. 158 - 184
Publisher: Cambridge University Press
Print publication year: 2009

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References

Hebbel, RP. Beyond hemoglobin polymerization: the red blood cell membrane and sickle disease pathophysiology. Blood. 1991;77(2):214–237.Google ScholarPubMed
Perrotta, S, Gallagher, PG, Mohandas, N. Hereditary spherocytosis. Lancet. 2008;372:1411–1426.Google Scholar
Hebbel, RP. The sickle erythrocyte in double jeopardy: autooxidation and iron decompartmentalization. Semin Hematol. 1990;27(1):51–69.Google Scholar
Asakura, T, Agarwal, PL, Relman, DA, et al. Mechanical instability of the oxy-form of sickle haemoglobin. Nature. 1973;244(5416):437–438.CrossRefGoogle ScholarPubMed
MacDonald, VW, Charache, S. Drug-induced oxidation and precipitation of hemoglobins A, S and C. Biochim Biophys Acta. 1982;701(1):39–44.CrossRefGoogle ScholarPubMed
Schrier, SL. Thalassemia: pathophysiology of red cell changes. Annu Rev Med. 1994;45:211–218.CrossRefGoogle ScholarPubMed
Shinar, E, Rachmilewitz, EA. Haemoglobinopathies and red cell membrane function. Baillieres Clin Haematol. 1993;6(2):357–369.CrossRefGoogle ScholarPubMed
Chiu, D, Lubin, B. Oxidative hemoglobin denaturation and RBC destruction: the effect of heme on red cell membranes. Semin Hematol. 1989;26(2):128–135.Google ScholarPubMed
Hebbel, RP, Eaton, JW. Pathobiology of heme interaction with the erythrocyte membrane. Semin Hematol. 1989;26(2):136–149.Google ScholarPubMed
Rice-Evans C, , Omorphos, SC, Baysal, E. Sickle cell membranes and oxidative damage. Biochem J. 1986;237(1):265–269.CrossRefGoogle ScholarPubMed
Marva, E, Hebbel, RP. Denaturing interaction between sickle hemoglobin and phosphatidylserine liposomes. Blood. 1994;83(1):242–249.Google ScholarPubMed
Sugihara, T, Repka, T, Hebbel, RP. Detection, characterization, and bioavailability of membrane-associated iron in the intact sickle red cell. J Clin Invest. 1992;90(6):2327–2332.CrossRefGoogle ScholarPubMed
Das, SK, Nair, RC. Superoxide dismutase, glutathione peroxidase, catalase and lipid peroxidation of normal and sickled erythrocytes. Br J Haematol. 1980;44(1):87–92.CrossRefGoogle ScholarPubMed
Chiu, D, Lubin, B. Abnormal vitamin E and glutathione peroxidase levels in sickle cell anemia: evidence for increased susceptibility to lipid peroxidation in vivo. J Lab Clin Med. 1979;94(4):542–548.Google ScholarPubMed
Schacter, LP, DelVillano, BC, Gordon, EM, Klein, BL. Red cell superoxide dismutase and sickle cell anemia symptom severity. Am J Hematol. 1985;19(2):137–144.CrossRefGoogle ScholarPubMed
Browne, P, Shalev, O, Hebbel, RP. The molecular pathobiology of cell membrane iron: the sickle red cell as a model. Free Radic Biol Med. 1998;24(6):1040–1048.CrossRefGoogle Scholar
Scott, MD, Eaton, JW. Thalassaemic erythrocytes: cellular suicide arising from iron and glutathione-dependent oxidation reactions?Br J Haematol. 1995;91(4):811–819.CrossRefGoogle ScholarPubMed
Tavazzi, D, Duca, L, Graziadei, G, Comino, A, Fiorelli, G, Cappellini, MD. Membrane-bound iron contributes to oxidative damage of beta-thalassaemia intermedia erythrocytes. Br J Haematol. 2001;112(1):48–50.CrossRefGoogle ScholarPubMed
Repka, T, Shalev, O, Reddy, R, et al. Nonrandom association of free iron with membranes of sickle and beta-thalassemic erythrocytes. Blood. 1993;82(10):3204–3210.Google ScholarPubMed
Asakura, T, Minakata, K, Adachi, K, Russell, MO, Schwartz, E. Denatured hemoglobin in sickle erythrocytes. J Clin Invest. 1977;59(4):633–640.CrossRefGoogle ScholarPubMed
Kuross, SA, Hebbel, RP. Nonheme iron in sickle erythrocyte membranes: association with phospholipids and potential role in lipid peroxidation. Blood. 1988;72(4):1278–1285.Google ScholarPubMed
Waugh, SM, Willardson, BM, Kannan, R, Labotka, RJ, Low, PS. Heinz bodies induce clustering of band 3, glycophorin, and ankyrin in sickle cell erythrocytes. J Clin Invest. 1986;78(5):1155–1160.CrossRefGoogle ScholarPubMed
Cappellini, MD, Tavazzi, D, Duca, L, et al. Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in beta-thalassaemia intermedia. Br J Haematol. 1999;104(3):504–512.CrossRefGoogle ScholarPubMed
Mannu, F, Arese, P, Cappellini, MD, et al. Role of hemichrome binding to erythrocyte membrane in the generation of band-3 alterations in beta-thalassemia intermedia erythrocytes. Blood. 1995;86(5):2014–2020.Google ScholarPubMed
Low, PS, Waugh, SM, Zinke, K, Drenckhahn, D. The role of hemoglobin denaturation and band 3 clustering in red blood cell aging. Science. 1985;227(4686):531–533.CrossRefGoogle ScholarPubMed
Kuross, SA, Rank, BH, Hebbel, RP. Excess heme in sickle erythrocyte inside-out membranes: possible role in thiol oxidation. Blood. 1988;71(4):876–882.Google ScholarPubMed
Hartley, A, Davies, MJ, Rice-Evans C, . Desferrioxamine and membrane oxidation: radical scavenger or iron chelator?Biochem Soc Trans. 1989;17(6):1002–1003.CrossRefGoogle ScholarPubMed
Shalev, O, Hebbel, RP. Extremely high avidity association of Fe(III) with the sickle red cell membrane. Blood. 1996;88(1):349–352.Google ScholarPubMed
Repka, T, Hebbel, RP. Hydroxyl radical formation by sickle erythrocyte membranes: role of pathologic iron deposits and cytoplasmic reducing agents. Blood. 1991;78(10):2753–2758.Google ScholarPubMed
Liu, SC, Yi, SJ, Mehta, JR, et al. Red cell membrane remodeling in sickle cell anemia. Sequestration of membrane lipids and proteins in Heinz bodies. J Clin Invest. 1996;97(1):29–36.CrossRefGoogle ScholarPubMed
Shalev, O, Repka, T, Goldfarb, A, et al. Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo. Blood. 1995;86(5):2008–2013.Google ScholarPubMed
Browne, PV, Shalev, O, Kuypers, FA, et al. Removal of erythrocyte membrane iron in vivo ameliorates the pathobiology of murine thalassemia. J Clin Invest. 1997;100(6):1459–1464.CrossRefGoogle ScholarPubMed
Shalev, O, Hebbel, RP. Catalysis of soluble hemoglobin oxidation by free iron on sickle red cell membranes. Blood. 1996;87(9):3948–3952.Google ScholarPubMed
Franceschi, L, Shalev, O, Piga, A, et al. Deferiprone therapy in homozygous human beta-thalassemia removes erythrocyte membrane free iron and reduces KCl cotransport activity. J Lab Clin Med. 1999;133(1):64–69.CrossRefGoogle ScholarPubMed
Advani, R, Sorenson, S, Shinar, E, Lande, W, Rachmilewitz, E, Schrier, SL. Characterization and comparison of the red blood cell membrane damage in severe human alpha- and beta-thalassemia. Blood. 1992;79(4):1058–1063.Google ScholarPubMed
Schrier, SL, Rachmilewitz, E, Mohandas, N. Cellular and membrane properties of alpha and beta thalassemic erythrocytes are different: implication for differences in clinical manifestations. Blood. 1989;74(6):2194–2202.Google ScholarPubMed
Scott, MD, Berg, JJ, Repka, T, et al. Effect of excess alpha-hemoglobin chains on cellular and membrane oxidation in model beta-thalassemic erythrocytes. J Clin Invest. 1993;91(4):1706–1712.CrossRefGoogle ScholarPubMed
Shinar, E, Rachmilewitz, EA, Lux, SE. Differing erythrocyte membrane skeletal protein defects in alpha and beta thalassemia. J Clin Invest. 1989;83(2):404–410.CrossRefGoogle ScholarPubMed
Yuan, J, Bunyaratvej, A, Fucharoen, S, Fung, C, Shinar, E, Schrier, SL. The instability of the membrane skeleton in thalassemic red blood cells. Blood. 1995;86(10):3945–3950.Google ScholarPubMed
Shinar, E, Shalev, O, Rachmilewitz, EA, Schrier, SL. Erythrocyte membrane skeleton abnormalities in severe beta-thalassemia. Blood. 1987;70(1):158–164.Google ScholarPubMed
Eisinger, J, Flores, J, Salhany, JM. Association of cytosol hemoglobin with the membrane in intact erythrocytes. Proc Natl Acad Sci USA. 1982;79(2):408–412.CrossRefGoogle ScholarPubMed
Salhany, JM, Cordes, KA, Gaines, ED. Light-scattering measurements of hemoglobin binding to the erythrocyte membrane. Evidence for transmembrane effects related to a disulfonic stilbene binding to band 3. Biochemistry. 1980;19(7):1447–1454.CrossRefGoogle ScholarPubMed
Shaklai, N, Yguerabide, J, Ranney, HM. Classification and localization of hemoglobin binding sites on the red blood cell membrane. Biochemistry. 1977;16(25):5593–5597.CrossRefGoogle ScholarPubMed
Shaklai, N, Yguerabide, J, Ranney, HM. Interaction of hemoglobin with red blood cell membranes as shown by a fluorescent chromophore. Biochemistry. 1977;16(25):5585–5592.CrossRefGoogle ScholarPubMed
Bank, A, Mears, G, Weiss, R, Donnell, JV, Natta, C. Preferential binding of beta s globin chains associated with stroma in sickle cell disorders. J Clin Invest. 1974;54(4):805–809.CrossRefGoogle Scholar
Fischer, S, Nagel, RL, Bookchin, RM, Roth, EF, Tellez-Nagel I, . The binding of hemoglobin to membranes of normal and sickle erythrocytes. Biochim Biophys Acta. 1975;375(3):422–433.CrossRefGoogle ScholarPubMed
Shaklai, N, Sharma, VS, Ranney, HM. Interaction of sickle cell hemoglobin with erythrocyte membranes. Proc Natl Acad Sci USA. 1981;78(1):65–68.CrossRefGoogle ScholarPubMed
Klipstein, FA, Ranney, HM. Electrophoretic components of the hemoglobin of red cell membranes. J Clin Invest. 1960;39:1894–1899.CrossRefGoogle ScholarPubMed
Schluter, K, Drenckhahn, D. Co-clustering of denatured hemoglobin with band 3: its role in binding of autoantibodies against band 3 to abnormal and aged erythrocytes. Proc Natl Acad Sci USA. 1986;83(16):6137–6141.CrossRefGoogle ScholarPubMed
Yuan, J, Kannan, R, Shinar, E, Rachmilewitz, EA, Low, PS. Isolation, characterization, and immunoprecipitation studies of immune complexes from membranes of beta-thalassemic erythrocytes. Blood. 1992;79(11):3007–3013.Google ScholarPubMed
Liu, SC, Derick, LH, Zhai, S, Palek, J. Uncoupling of the spectrin-based skeleton from the lipid bilayer in sickled red cells. Science. 1991;252(5005):574–576.CrossRefGoogle ScholarPubMed
Corbett, JD, Golan, . Band 3 and glycophorin are progressively aggregated in density-fractionated sickle and normal red blood cells. Evidence from rotational and lateral mobility studies. J Clin Invest. 1993;91(1):208–217.CrossRefGoogle ScholarPubMed
Platt, OS, Falcone, JF. Membrane protein interactions in sickle red blood cells: evidence of abnormal protein 3 function. Blood. 1995;86(5):1992–1998.Google ScholarPubMed
Platt, OS, Falcone, JF, Lux, SE. Molecular defect in the sickle erythrocyte skeleton. Abnormal spectrin binding to sickle inside-our vesicles. J Clin Invest. 1985;75(1):266–271.CrossRefGoogle ScholarPubMed
Platt, OS, Falcone, JF. Membrane protein lesions in erythrocytes with Heinz bodies. J Clin Invest. 1988;82(3):1051–1058.CrossRefGoogle ScholarPubMed
Rank, BH, Carlsson, J, Hebbel, RP. Abnormal redox status of membrane-protein thiols in sickle erythrocytes. J Clin Invest. 1985;75(5):1531–1537.CrossRefGoogle ScholarPubMed
Schwartz, RS, Rybicki, AC, Heath, RH, Lubin, BH. Protein 4.1 in sickle erythrocytes. Evidence for oxidative damage. J Biol Chem. 1987;262(32):15666–15672.Google ScholarPubMed
Shaklai, N, Frayman, B, Fortier, N, Snyder, M. Crosslinking of isolated cytoskeletal proteins with hemoglobin: a possible damage inflicted to the red cell membrane. Biochim Biophys Acta. 1987;915(3):406–414.CrossRefGoogle ScholarPubMed
Allan, D, Limbrick, AR, Thomas, P, Westerman, MP. Microvesicles from sickle erythrocytes and their relation to irreversible sickling. Br J Haematol. 1981;47(3):383–390.CrossRefGoogle ScholarPubMed
Allan, D, Limbrick, AR, Thomas, P, Westerman, MP. Release of spectrin-free spicules on reoxygenation of sickled erythrocytes. Nature. 1982;295(5850):612–613.CrossRefGoogle ScholarPubMed
Butikofer, P, Kuypers, FA, Xu, CM, Chiu, DT, Lubin, B. Enrichment of two glycosyl-phosphatidylinositol-anchored proteins, acetylcholinesterase and decay accelerating factor, in vesicles released from human red blood cells. Blood. 1989;74(5):1481–1485.Google ScholarPubMed
Padilla, F, Bromberg, PA, Jensen, WN. The sickle-unsickle cycle: a cause of cell fragmentation leading to permanently deformed cells. Blood. 1973;41(5):653–660.Google ScholarPubMed
Test, ST, Butikofer, P, Yee, MC, Kuypers, FA, Lubin, B. Characterization of the complement sensitivity of calcium loaded human erythrocytes. Blood. 1991;78(11):3056–3065.Google ScholarPubMed
Test, ST, Woolworth, VS. Defective regulation of complement by the sickle erythrocyte: evidence for a defect in control of membrane attack complex formation. Blood. 1994;83(3):842–852.Google ScholarPubMed
Turrini, F, Arese, P, Yuan, J, Low, PS. Clustering of integral membrane proteins of the human erythrocyte membrane stimulates autologous IgG binding, complement deposition, and phagocytosis. J Biol Chem. 1991;266(35):23611–23617.Google ScholarPubMed
Ataga, KI, Key, NS. Hypercoagulability in sickle cell disease: new approaches to an old problem. Hematology Am Soc Hematol Educ Program. 2007;2007:91–96.Google Scholar
Wagner, GM, Chiu, DT, Yee, MC, Lubin, BH. Red cell vesiculation – a common membrane physiologic event. J Lab Clin Med. 1986;108(4):315–324.Google ScholarPubMed
Westerman, MP, Cole, ER, Wu, K. The effect of spicules obtained from sickle red cells on clotting activity. Br J Haematol. 1984;56(4):557–562.CrossRefGoogle ScholarPubMed
Franck, PF, Bevers, EM, Lubin, BH, et al. Uncoupling of the membrane skeleton from the lipid bilayer. The cause of accelerated phospholipid flip-flop leading to an enhanced procoagulant activity of sickled cells. J Clin Invest. 1985;75(1):183–190.CrossRefGoogle Scholar
Lane, PA, Connell, JL, Marlar, RA. Erythrocyte membrane vesicles and irreversibly sickled cells bind protein S. Am J Hematol. 1994;47(4):295–300.CrossRefGoogle ScholarPubMed
Bertles, JF, Dobler, J. Reversible and irreversible sickling: a distinction by electron microscopy. Blood. 1969;33(6):884–898.Google ScholarPubMed
Bertles, JF, Milner, PF. Irreversibly sickled erythrocytes: a consequence of the heterogeneous distribution of hemoglobin types in sickle-cell anemia. J Clin Invest. 1968;47(8):1731–1741.CrossRefGoogle ScholarPubMed
Serjeant, GR. Irreversibly sickled cells and splenomegaly in sickle-cell anaemia. Br J Haematol. 1970;19(5):635–641.CrossRefGoogle ScholarPubMed
Serjeant, GR, Serjeant, BE, Milner, PF. The irreversibly sickled cell; a determinant of haemolysis in sickle cell anaemia. Br J Haematol. 1969;17(6):527–533.CrossRefGoogle ScholarPubMed
Glader, BE, Nathan, DG. Cation permeability alterations during sickling: relationship to cation composition and cellular hydration of irreversibly sickled cells. Blood. 1978;51(5):983–989.Google ScholarPubMed
Horiuchi, K, Ballas, SK, Asakura, T. The effect of deoxygenation rate on the formation of irreversibly sickled cells. Blood. 1988;71(1):46–51.Google ScholarPubMed
Jensen, M, Shohet, SB, Nathan, DG. The role of red cell energy metabolism in the generation of irreversibly sickled cells in vitro. Blood. 1973;42(6):835–842.Google ScholarPubMed
Nash, GB, Johnson, CS, Meiselman, HJ. Rheologic impairment of sickle RBCs induced by repetitive cycles of deoxygenation-reoxygenation. Blood. 1988;72(2):539–545.Google ScholarPubMed
Lux, SE, John, KM, Karnovsky, MJ. Irreversible deformation of the spectrin-actin lattice in irreversibly sickled cells. J Clin Invest. 1976;58(4):955–963.CrossRefGoogle ScholarPubMed
Liu, SC, Derick, LH, Palek, J. Dependence of the permanent deformation of red blood cell membranes on spectrin dimer-tetramer equilibrium: implication for permanent membrane deformation of irreversibly sickled cells. Blood. 1993;81(2):522–528.Google ScholarPubMed
Bencsath, FA, Shartava, A, Monteiro, CA, Goodman, SR. Identification of the disulfide-linked peptide in irreversibly sickled cell beta-actin. Biochemistry. 1996;35(14):4403–4408.CrossRefGoogle ScholarPubMed
Shartava, A, Monteiro, CA, Bencsath, FA, et al. A posttranslational modification of beta-actin contributes to the slow dissociation of the spectrin-protein 4.1-actin complex of irreversibly sickled cells. J Cell Biol. 1995;128(5):805–818.CrossRefGoogle ScholarPubMed
Chiu, D, Lubin, B, Shohet, SB. Erythrocyte membrane lipid reorganization during the sickling process. Br J Haematol. 1979;41(2):223–234.CrossRefGoogle ScholarPubMed
Wetterstroem, N, Brewer, GJ, Warth, JA, Mitchinson, A, Near, K. Relationship of glutathione levels and Heinz body formation to irreversibly sickled cells in sickle cell anemia. J Lab Clin Med. 1984;103(4):589–596.Google ScholarPubMed
Schroeder, F, Woodford, JK, Kavecansky, J, Wood, WG, Joiner, C. Cholesterol domains in biological membranes. Mol Membr Biol. 1995;12(1):113–119.CrossRefGoogle ScholarPubMed
Daleke, DL. Phospholipid flippases. J Biol Chem. 2007;282(2):821–825.CrossRefGoogle ScholarPubMed
Daleke, DL. Regulation of phospholipid asymmetry in the erythrocyte membrane. Curr Opin Hematol. 2008;15(3):191–195.CrossRefGoogle ScholarPubMed
Sims, PJ, Wiedmer, T. Unraveling the mysteries of phospholipid scrambling. Thromb Haemost. 2001;86(1):266–275.Google ScholarPubMed
Schlegel, RA, Williamson, P. P.S. to PS (phosphatidylserine)–pertinent proteins in apoptotic cell clearance. SciSTK. 2007; 2007(408):pe57.Google Scholar
Setty, BN, Betal, SG. Microvascular endothelial cells express a phosphatidylserine receptor: a functionally active receptor for phosphatidylserine-positive erythrocytes. Blood. 2008;111(2):905–914.CrossRefGoogle ScholarPubMed
Kuypers, FA. Membrane lipid alterations in hemoglobinopathies. Hematology Am Soc Hematol Educ Program. 2007;2007:68–73.Google Scholar
Yeung, T, Gilbert, GE, Shi, J, Silvius, J, Kapus, A, Grinstein, S. Membrane phosphatidylserine regulates surface charge and protein localization. Science. 2008;319(5860):210–213.CrossRefGoogle ScholarPubMed
Kuypers, FA, Lewis, RA, Hua, M, et al. Detection of altered membrane phospholipid asymmetry in subpopulations of human red blood cells using fluorescently labeled annexin V. Blood. 1996;87(3):1179–1187.Google ScholarPubMed
Lubin, B, Chiu, D, Bastacky, J, Roelofsen, B, Deenen, LL. Abnormalities in membrane phospholipid organization in sickled erythrocytes. J Clin Invest. 1981;67(6):1643–1649.CrossRefGoogle ScholarPubMed
Wood, BL, Gibson, DF, Tait, JF. Increased erythrocyte phosphatidylserine exposure in sickle cell disease: flow-cytometric measurement and clinical associations. Blood. 1996;88(5):1873–1880.Google ScholarPubMed
Kuypers, FA, Schott, MA, Scott, MD. Phospholipid composition and organization in model beta-thalassemic erythrocytes. Am J Hematol. 1996;51(1):45–54.3.0.CO;2-7>CrossRefGoogle ScholarPubMed
Kuypers, FA, Yuan, J, Lewis, RA, et al. Membrane phospholipid asymmetry in human thalassemia. Blood. 1998;91(8):3044–3051.Google ScholarPubMed
Hebbel, RP, Schwartz, RS, Mohandas, N. The adhesive sickle erythrocyte: cause and consequence of abnormal interactions with endothelium, monocytes/macrophages and model membranes. Clin Haematol. 1985;14(1):141–161.Google ScholarPubMed
Schwartz, RS, Tanaka, Y, Fidler, IJ, Chiu, DT, Lubin, B, Schroit, AJ. Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to cultured human peripheral blood monocytes. J Clin Invest. 1985;75(6):1965–1972.CrossRefGoogle ScholarPubMed
Jong, K, Larkin, SK, Styles, , Bookchin, RM, Kuypers, FA. Characterization of the phosphatidylserine-exposing subpopulation of sickle cells. Blood. 2001;98(3):860–867.CrossRefGoogle ScholarPubMed
Yasin, Z, Witting, S, Palascak, MB, Joiner, CH, Rucknagel, DL, Franco, RS. Phosphatidylserine externalization in sickle red blood cells: associations with cell age, density, and hemoglobin F. Blood. 2003;102(1):365–370.CrossRefGoogle ScholarPubMed
Basu, S, Banerjee, D, Chandra, S, Chakrabarti, A. Loss of phospholipid membrane asymmetry and sialylated glycoconjugates from erythrocyte surface in haemoglobin E beta-thalassaemia. Br J Haematol. 2008;141(1):92–99.CrossRefGoogle ScholarPubMed
Horne, MK 3rd, Cullinane, AM, Merryman, PK, Hoddeson, EK. The effect of red blood cells on thrombin generation. Br J Haematol. 2006;133(4):403–408.CrossRefGoogle ScholarPubMed
Stuart, MJ, Setty, BN. Hemostatic alterations in sickle cell disease: relationships to disease pathophysiology. Pediatr Pathol Mol Med. 2001;20(1):27–46.CrossRefGoogle ScholarPubMed
Bezeaud, A, Venisse, L, Helley, D, Trichet, C, Girot, R, Guillin, MC. Red blood cells from patients with homozygous sickle cell disease provide a catalytic surface for factor Va inactivation by activated protein C. Br J Haematol. 2002;117(2):409–413.CrossRefGoogle ScholarPubMed
Zwaal, RF, Schroit, AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood. 1997;89(4):1121–1132.Google ScholarPubMed
Styles, L, Jong, K, Vichinsky, E, Lubin, B, Adams, R, Kuypers, FA. Increased RBC phosphatidylserine exposure in sickle cell disease patients at risk for stroke by transcranial Doppler screening. Blood. 1997;90:604a.Google Scholar
Jong, K, Emerson, RK, Butler, J, Bastacky, J, Mohandas, N, Kuypers, FA. Short survival of phosphatidylserine-exposing red blood cells in murine sickle cell anemia. Blood. 2001;98(5):1577–1584.CrossRefGoogle ScholarPubMed
Ataga, KI, Cappellini, MD, Rachmilewitz, EA. Beta-thalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol. 2007;139(1):3–13.CrossRefGoogle ScholarPubMed
Panigrahi, I, Agarwal, S. Thromboembolic complications in beta-thalassemia: Beyond the horizon. Thromb Res. 2007;120(6):783–789.CrossRefGoogle Scholar
Setty, BN, Rao, AK, Stuart, MJ. Thrombophilia in sickle cell disease: the red cell connection. Blood. 2001;98(12):3228–3233.CrossRefGoogle ScholarPubMed
Setty, BN, Kulkarni, S, Rao, AK, Stuart, MJ. Fetal hemoglobin in sickle cell disease: relationship to erythrocyte phosphatidylserine exposure and coagulation activation. Blood. 2000;96(3):1119–1124.Google ScholarPubMed
Atichartakarn, V, Angchaisuksiri, P, Aryurachai, K, et al. Relationship between hypercoagulable state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/beta-thalassaemic patients. Br J Haematol. 2002;118(3):893–898.CrossRefGoogle ScholarPubMed
Lang, F, Lang, KS, Lang, PA, Huber, SM, Wieder, T. Mechanisms and significance of eryptosis. Antioxid Redox Signal. 2006;8(7–8):1183–1192.CrossRefGoogle ScholarPubMed
Vance, JE, Steenbergen, R. Metabolism and functions of phosphatidylserine. Prog Lipid Res. 2005;44(4):207–234.CrossRefGoogle ScholarPubMed
Wang, RH, Phillips, G, Medof, ME, Mold, C. Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients. J Clin Invest. 1993;92(3):1326–1335.CrossRefGoogle ScholarPubMed
Neidlinger, NA, Larkin, SK, Bhagat, A, Victorino, GP, Kuypers, FA. Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction. J Biol Chem. 2006;281(2):775–781.CrossRefGoogle ScholarPubMed
Styles, , Aarsman, AJ, Vichinsky, EP, Kuypers, FA. Secretory phospholipase A(2) predicts impending acute chest syndrome in sickle cell disease. Blood. 2000;96(9):3276–3278.Google ScholarPubMed
Styles, , Abboud, M, Larkin, S, Lo, M, Kuypers, FA. Transfusion prevents acute chest syndrome predicted by elevated secretory phospholipase A2. Br J Haematol. 2007;136(2):343–344.CrossRefGoogle ScholarPubMed
Jong, K, Geldwerth, D, Kuypers, FA. Oxidative damage does not alter membrane phospholipid asymmetry in human erythrocytes. Biochemistry. 1997;36(22):6768–6776.CrossRefGoogle Scholar
Blumenfeld, N, Zachowski, A, Galacteros, F, Beuzard, Y, Devaux, PF. Transmembrane mobility of phospholipids in sickle erythrocytes: effect of deoxygenation on diffusion and asymmetry. Blood. 1991;77(4):849–854.Google ScholarPubMed
Jong, K, Kuypers, FA. Sulphydryl modifications alter scramblase activity in murine sickle cell disease. Br J Haematol. May 2006;133(4):427–432.CrossRefGoogle ScholarPubMed
Devaux, PF, Morris, R. Transmembrane asymmetry and lateral domains in biological membranes. Traffic. 2004;5(4):241–246.CrossRefGoogle ScholarPubMed
Eaton, WA, Hofrichter, J. Hemoglobin S gelation and sickle cell disease. Blood. 1987;70(5):1245–1266.Google ScholarPubMed
Eaton, WA, Hofrichter, J. Sickle cell hemoglobin polymerization. Adv Protein Chem. 1990;40:63–279.CrossRefGoogle ScholarPubMed
Noguchi, CT, Rodgers, GP, Schechter, AN. Intracellular polymerization. Disease severity and therapeutic predictions. Ann NY Acad Sci. 1989;565:75–82.CrossRefGoogle ScholarPubMed
Kaul, DK, Fabry, ME, Nagel, RL. Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: pathophysiological implications. Proc Natl Acad Sci USA. 1989;86(9):3356–3360.CrossRefGoogle ScholarPubMed
Kaul, DK, Chen, D, Zhan, J. Adhesion of sickle cells to vascular endothelium is critically dependent on changes in density and shape of the cells. Blood. 1994;83(10):3006–3017.Google ScholarPubMed
Morris, CL, Rucknagel, DL, Joiner, CH. Deoxygenation-induced changes in sickle cell-sickle cell adhesion. Blood. 1993;81(11):3138–3145.Google ScholarPubMed
Platt, OS. Exercise-induced hemolysis in sickle cell anemia: shear sensitivity and erythrocyte dehydration. Blood. 1982;59(5):1055–1060.Google ScholarPubMed
Hiruma, H, Noguchi, CT, Uyesaka, N, Schechter, AN, Rodgers, GP. Contributions of sickle hemoglobin polymer and sickle cell membranes to impaired filterability. Am J Physiol. 1995;268(5 Pt 2):H2003–2008.Google ScholarPubMed
Hasegawa, S, Hiruma, H, Uyesaka, N, Noguchi, CT, Schechter, AN, Rodgers, GP. Filterability of mixtures of sickle and normal erythrocytes. Am J Hematol. 1995;50(2):91–97.CrossRefGoogle ScholarPubMed
Dong, C, Chadwick, RS, Schechter, AN. Influence of sickle hemoglobin polymerization and membrane properties on deformability of sickle erythrocytes in the microcirculation. Biophys J. 1992;63(3):774–783.CrossRefGoogle ScholarPubMed
Fabry, ME, Nagel, RL. Heterogeneity of red cells in the sickler: a characteristic with practical clinical and pathophysiological implications. Blood Cells. 1982;8(1):9–15.Google ScholarPubMed
Mohandas, N, Ballas, S. Erythrocyte density and heterogeneity. In: Embury, S, Hebbel, RP, Mohandas, N, Steinberg, MH, eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York: Raven Press; 1994.Google Scholar
Mohandas, N, Johnson, A, Wyatt, J, et al. Automated quantitation of cell density distribution and hyperdense cell fraction in RBC disorders. Blood. 1989;74(1):442–447.Google ScholarPubMed
Mohandas, N, Kim, YR, Tycko, DH, Orlik, J, Wyatt, J, Groner, W. Accurate and independent measurement of volume and hemoglobin concentration of individual red cells by laser light scattering. Blood. 1986;68(2):506–513.Google ScholarPubMed
Tosteson, D, Carlen, E, Dunham, ET.The effects of sickling on ion transport I. Effect of sickling on potassium transport. J. Gen. Physiol. 1955;39:31–54.CrossRefGoogle ScholarPubMed
Tosteson, D, Shea, et al. The efftects of sickling on ion transport II. The effects of sickling on sodium and cesium transport. J. Gen. Physiol. 1955;39:55–67.CrossRefGoogle Scholar
Tosteson, D, Shea, et al. Potassium and sodium in red blood cells in sickle cell anemia. J Clin Invest. 1952;48:406–411.CrossRefGoogle Scholar
Glader, BE, Lux, SE, Muller-Soyano A, , Platt, OS, Propper, RD, Nathan, DG. Energy reserve and cation composition of irreversibly sickled cells in vivo. Br J Haematol. 1978;40(4):527–532.CrossRefGoogle ScholarPubMed
Clark, MR, Morrison, CE, Shohet, SB. Monovalent cation transport in irreversibly sickled cells. J Clin Invest. 1978;62(2):329–337.CrossRefGoogle ScholarPubMed
Bookchin, RM, Etzion, Z, Sorette, M, Mohandas, N, Skepper, JN, Lew, VL. Identification and characterization of a newly recognized population of high-Na+, low-K+, low-density sickle and normal red cells. Proc Natl Acad Sci USA. 2000;97(14):8045–8050.CrossRefGoogle ScholarPubMed
Etzion, Z, Lew, VL, Bookchin, RM. K(86Rb) transport heterogeneity in the low-density fraction of sickle cell anemia red blood cells. Am J Physiol. 1996;271(4 Pt 1):C1111–1121.CrossRefGoogle ScholarPubMed
Holtzclaw, JD, Jiang, M, Yasin, Z, Joiner, CH, Franco, RS. Rehydration of high-density sickle erythrocytes in vitro. Blood. 2002;100(8):3017–3025.CrossRefGoogle ScholarPubMed
Franco, RS, Yasin, Z, Lohmann, JM, et al. The survival characteristics of dense sickle cells. Blood. 2000;96(10):3610–3617.Google ScholarPubMed
Amer, J, Etzion, Z, Bookchin, RM, Fibach, E. Oxidative status of valinomycin–resistant normal, beta-thalassemia and sickle red blood cells. Biochim Biophys Acta. 2006;1760(5):793–799.CrossRefGoogle ScholarPubMed
Fabry, ME, Benjamin, L, Lawrence, C, Nagel, RL. An objective sign in painful crisis in sickle cell anemia: the concomitant reduction of high density red cells. Blood. 1984;64(2):559–563.Google ScholarPubMed
Lawrence, C, Fabry, ME, Nagel, RL. Red cell distribution width parallels dense red cell disappearance during painful crises in sickle cell anemia. J Lab Clin Med. 1985;105(6):706–710.Google ScholarPubMed
Lawrence, C, Fabry, ME. Objective indices of sickle cell painful crisis: decrease in RDW and percent dense cells and increase in ESR and fibrinogen. Prog Clin Biol Res. 1987;240:329–336.Google ScholarPubMed
Ballas, SK, Smith, ED. Red blood cell changes during the evolution of the sickle cell painful crisis. Blood. 1992;79(8):2154–2163.Google ScholarPubMed
Fabry, ME, Mears, JG, Patel, P, et al. Dense cells in sickle cell anemia: the effects of gene interaction. Blood. 1984;64(5):1042–1046.Google ScholarPubMed
Embury, SH, Clark, MR, Monroy, G, Mohandas, N. Concurrent sickle cell anemia and alpha-thalassemia. Effect on pathological properties of sickle erythrocytes. J Clin Invest. 1984;73(1):116–123.CrossRefGoogle ScholarPubMed
Ballas, SK. Sickle cell anemia with few painful crises is characterized by decreased red cell deformability and increased number of dense cells. Am J Hematol. 1991;36(2):122–130.CrossRefGoogle ScholarPubMed
Lande, WM, Andrews, DL, Clark, MR, et al. The incidence of painful crisis in homozygous sickle cell disease: correlation with red cell deformability. Blood. 1988;72(6):2056–2059.Google ScholarPubMed
Ballas, SK, Larner, J, Smith, ED, Surrey, S, Schwartz, E, Rappaport, EF. Rheologic predictors of the severity of the painful sickle cell crisis. Blood. 1988;72(4):1216–1223.Google ScholarPubMed
Billett, HH, Kim, K, Fabry, ME, Nagel, RL. The percentage of dense red cells does not predict incidence of sickle cell painful crisis. Blood. 1986;68(1):301–303.Google Scholar
Brugnara, C, Gee, B, Armsby, CC, et al. Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease. J Clin Invest. 1996;97(5):1227–1234.CrossRefGoogle ScholarPubMed
Franceschi, L, Beuzard, Y, Jouault, H, Brugnara, C. Modulation of erythrocyte potassium chloride cotransport, potassium content, and density by dietary magnesium intake in transgenic SAD mouse. Blood. 1996;88(7):2738–2744.Google ScholarPubMed
Franceschi, L, Bachir, D, Galacteros, F, et al. Oral magnesium pidolate: effects of long-term administration in patients with sickle cell disease. Br J Haematol. 2000;108(2):284–289.CrossRefGoogle ScholarPubMed
Rivera, A. Reduced sickle erythrocyte dehydration in vivo by endothelin-1 receptor antagonists. Am J Physiol Cell Physiol. 2007;293:in press.Google ScholarPubMed
Stocker, JW, Franceschi, L, McNaughton-Smith, GA, Corrocher, R, Beuzard, Y, Brugnara, C. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood. 2003;101(6):2412–2418.CrossRefGoogle ScholarPubMed
Ataga, KI, Smith, WR, Castro, LM et al. Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood. 2008;111(8):3991–3997.CrossRefGoogle Scholar
Bookchin, RM, Lew, VL. Effects of a ‘sickling pulse’ on the calcium and potassium permeabilities of intact, sickle trait red cells [proceedings]. J Physiol. 1978;284:93P–94P.Google Scholar
Roth, EF, Nagel, RL, Bookchin, RM. pH dependency of potassium efflux from sickled red cells. Am J Hematol. 1981;11(1):19–27.CrossRefGoogle ScholarPubMed
Berkowitz, LR, Orringer, EP. Passive sodium and potassium movements in sickle erythrocytes. Am J Physiol. 1985;249(3 Pt 1):C208–214.CrossRefGoogle ScholarPubMed
Joiner, CH, Platt, OS, Lux, SE. Cation depletion by the sodium pump in red cells with pathologic cation leaks. Sickle cells and xerocytes. J Clin Invest. 1986;78(6):1487–1496.CrossRefGoogle ScholarPubMed
Joiner, CH, Dew, A, Ge, DL. Deoxygenation-induced cation fluxes in sickle cells: relationship between net potassium efflux and net sodium influx. Blood Cells. 1988;13(3):339–358.Google ScholarPubMed
Joiner, CH. Deoxygenation-induced cation fluxes in sickle cells: II. Inhibition by stilbene disulfonates. Blood. 1990;76(1):212–220.Google ScholarPubMed
Joiner, CH, Gunn, RB, Frohlich, O. Anion transport in sickle red blood cells. Pediatr Res. 1990;28(6):587–590.CrossRefGoogle ScholarPubMed
Joiner, CH, Morris, CL, Cooper, ES. Deoxygenation-induced cation fluxes in sickle cells. III. Cation selectivity and response to pH and membrane potential. Am J Physiol. 1993;264(3 Pt 1):C734–744.CrossRefGoogle ScholarPubMed
Joiner, CH, Jiang, M, Franco, RS. Deoxygenation-induced cation fluxes in sickle cells. IV. Modulation by external calcium. Am J Physiol. 1995;269(2 Pt 1):C403–409.CrossRefGoogle ScholarPubMed
Mohandas, N, Rossi, ME, Clark, MR. Association between morphologic distortion of sickle cells and deoxygenation-induced cation permeability increase. Blood. 1986;68(2):450–454.Google ScholarPubMed
Ortiz, OE, Lew, VL, Bookchin, RM. Deoxygenation permeabilizes sickle cell anaemia red cells to magnesium and reverses its gradient in the dense cells. J Physiol. 1990;427:211–226.CrossRefGoogle ScholarPubMed
Rhoda, MD, Apovo, M, Beuzard, Y, Giraud, F. Ca2+ permeability in deoxygenated sickle cells. Blood. 1990;75(12):2453–2458.Google ScholarPubMed
Joiner, CH, Jiang, M, Claussen, WJ, Roszell, NJ, Yasin, Z, Franco, RS. Dipyridamole inhibits sickling-induced cation fluxes in sickle red blood cells. Blood. 2001;97(12):3976–3983.CrossRefGoogle ScholarPubMed
Clark, MR, Rossi, ME. Permeability characteristics of deoxygenated sickle cells. Blood. 1990;76(10):2139–2145.Google ScholarPubMed
Browning, JA, Robinson, HC, Ellory, JC, Gibson, JS. Deoxygenation-induced non-electrolyte pathway in red cells from sickle cell patients. Cell Physiol Biochem. 2007;19(1–4):165–174.CrossRefGoogle ScholarPubMed
Bookchin, RM, Ortiz, OE, Lew, VL. Evidence for a direct reticulocyte origin of dense red cells in sickle cell anemia. J Clin Invest. 1991;87(1):113–124.CrossRefGoogle ScholarPubMed
Clark, MR, Guatelli, JC, White, AT, Shohet, SB. Study on the dehydrating effect of the red cell Na+/K+-pump in nystatin-treated cells with varying Na+ and water contents. Biochim Biophys Acta. 1981;646(3):422–432.CrossRefGoogle ScholarPubMed
Lew, VL, Freeman, CJ, Ortiz, OE, Bookchin, RM. A mathematical model of the volume, pH, and ion content regulation in reticulocytes. Application to the pathophysiology of sickle cell dehydration. J Clin Invest. 1991;87(1):100–112.CrossRefGoogle ScholarPubMed
Gibson, JS, Stewart, GW, Ellory, JC. Effect of dimethyl adipimidate on K+ transport and shape change in red blood cells from sickle cell patients. FEBS Letters. 2000;480(2–3):179–183.CrossRefGoogle Scholar
Lubin, BH, Pena, V, Mentzer, WC, Bymun, E, Bradley, TB, Packer, L. Dimethyl adipimidate: a new antisickling agent. Proc Natl Acad Sci USA. 1975;72(1):43–46.CrossRefGoogle ScholarPubMed
Kavecansky, J, Schroeder, F, Joiner, CH. Deoxygenation-induced alterations in sickle cell membrane cholesterol exchange. Am J Physiol. 1995;269(5 Pt 1):C1105–1111.CrossRefGoogle ScholarPubMed
Sugihara, T, Yawata, Y, Hebbel, RP. Deformation of swollen erythrocytes provides a model of sickling-induced leak pathways, including a novel bromide-sensitive component. Blood. 1994;83(9):2684–2691.Google ScholarPubMed
Jones, GS, Knauf, PA. Mechanism of the increase in cation permeability of human erythrocytes in low-chloride media. Involvement of the anion transport protein capnophorin. J Gen Physiol. 1985;86(5):721–738.CrossRefGoogle ScholarPubMed
Bruce, LJ, Robinson, HC, Guizouarn, H, et al. Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1. Nat Genet. 2005;37(11):1258–1263.CrossRefGoogle ScholarPubMed
Hebbel, RP, Mohandas, N. Reversible deformation-dependent erythrocyte cation leak. Extreme sensitivity conferred by minimal peroxidation. Biophys J. 1991;60(3):712–715.CrossRefGoogle ScholarPubMed
Ney, PA, Christopher, MM, Hebbel, RP. Synergistic effects of oxidation and deformation on erythrocyte monovalent cation leak. Blood. 1990;75(5):1192–1198.Google ScholarPubMed
Johnson, RM, Gannon, SA. Erythrocyte cation permeability induced by mechanical stress: a model for sickle cell cation loss. Am J Physiol. 1990;259(5 Pt 1):C746–751.CrossRefGoogle ScholarPubMed
Johnson, RM. Membrane stress increases cation permeability in red cells. Biophys J. 1994;67(5):1876–1881.CrossRefGoogle ScholarPubMed
Johnson, RM, Tang, K. Induction of a Ca(2+)-activated K+ channel in human erythrocytes by mechanical stress. Biochim Biophys Acta. 1992;1107(2):314–318.CrossRefGoogle Scholar
Sugihara, T, Hebbel, RP. Exaggerated cation leak from oxygenated sickle red blood cells during deformation: evidence for a unique leak pathway. Blood. 1992;80(9):2374–2378.Google ScholarPubMed
Johnson, RM, Tang, K. DIDS inhibition of deformation-induced cation flux in human erythrocytes. Biochim Biophys Acta. 1993;1148(1):7–14.CrossRefGoogle ScholarPubMed
Clark, MR, Unger, RC, Shohet, SB. Monovalent cation composition and ATP and lipid content of irreversibly sickled cells. Blood. 1978;51:1169–1178.Google ScholarPubMed
Canessa, M, Fabry, ME, Suzuka, SM, Morgan, K, Nagel, RL. Na+/H+ exchange is increased in sickle cell anemia and young normal red cells. J Membr Biol. 1990;116(2):107–115.CrossRefGoogle Scholar
Canessa, M, Fabry, ME, Blumenfeld, N, Nagel, RL. Volume-stimulated, Cl(-)-dependent K+ efflux is highly expressed in young human red cells containing normal hemoglobin or HbS. J Membr Biol. 1987;97(2):97–105.CrossRefGoogle ScholarPubMed
Rivera, A, Ferreira, A, Bertoni, D, Romero, JR, Brugnara, C. Abnormal regulation of Mg2+ transport via Na/Mg exchanger in sickle erythrocytes. Blood. 2005;105(1):382–386.CrossRefGoogle ScholarPubMed
Joiner, CH, Jiang, M, Fathallah, H, Giraud, F, Franco, RS. Deoxygenation of sickle red blood cells stimulates KCl cotransport without affecting Na+/H+ exchange. Am J Physiol. 1998;274(6 Pt 1):C1466–1475.CrossRefGoogle Scholar
Eaton, JW, Skelton, TD, Swofford, HS, Kolpin, CE, Jacob, HS. Elevated erythrocyte calcium in sickle cell disease. Nature. 1973;246(5428):105–106.CrossRefGoogle ScholarPubMed
Palek, J, Thomae, M, Ozog, D. Red cell calcium content and transmembrane calcium movements in sickle cell anemia. J Lab Clin Med. 1977;89(6):1365–1374.Google ScholarPubMed
Engelmann, B, Duhm, J. Intracellular calcium content of human erythrocytes: relation to sodium transport systems. J Membr Biol. 1987;98(1):79–87.CrossRefGoogle ScholarPubMed
Lew, VL, Tsien, RY, Miner, C, Bookchin, RM. Physiological [Ca2+]i level and pump-leak turnover in intact red cells measured using an incorporated Ca chelator. Nature. 1982;298(5873):478–481.CrossRefGoogle ScholarPubMed
Murphy, E, Berkowitz, LR, Orringer, E, Levy, L, Gabel, SA, London, RE. Cytosolic free calcium levels in sickle red blood cells. Blood. 1987;69(5):1469–1474.Google ScholarPubMed
Bookchin, RM, Ortiz, OE, Somlyo, AV, et al. Calcium-accumulating inside-out vesicles in sickle cell anemia red cells. Trans Assoc Am Physicians. 1985;98:10–20.Google ScholarPubMed
Lew, VL, Hockaday, A, Sepulveda, MI, et al. Compartmentalization of sickle-cell calcium in endocytic inside-out vesicles. Nature. 1985;315(6020):586–589.CrossRefGoogle ScholarPubMed
Williamson, P, Puchulu, E, Penniston, JT, Westerman, MP, Schlegel, RA. Ca2+ accumulation and loss by aberrant endocytic vesicles in sickle erythrocytes. J Cell Physiol. 1992;152(1):1–9.CrossRefGoogle ScholarPubMed
Westerman, MP, Puchulu, E, Schlegel, RA, Salameh, M, Williamson, P. Intracellular Ca(2+)-containing vesicles in sickle cell disorders. J Lab Clin Med. 1994;124(3):416–420.Google ScholarPubMed
Bookchin, RM, Lew, VL. Effect of a ‘sickling pulse’ on calcium and potassium transport in sickle cell trait red cells. J Physiol. 1981;312:265–280.CrossRefGoogle ScholarPubMed
Etzion, Z, Tiffert, T, Bookchin, RM, Lew, VL. Effects of deoxygenation on active and passive Ca2+ transport and on the cytoplasmic Ca2+ levels of sickle cell anemia red cells. J Clin Invest. 1993;92(5):2489–2498.CrossRefGoogle ScholarPubMed
Tiffert, T, Spivak, JL, Lew, VL. Magnitude of calcium influx required to induce dehydration of normal human red cells. Biochim Biophys Acta. 1988;943(2):157–165.CrossRefGoogle ScholarPubMed
Horiuchi, K, Onyike, AE, Osterhout, ML. Sickling in vitro of reticulocytes from patients with sickle cell disease at venous oxygen tension. Exp Hematol. 1996;24(1):68–76.Google ScholarPubMed
Lew, VL, Ortiz, OE, Bookchin, RM. Stochastic nature and red cell population distribution of the sickling-induced Ca2+ permeability. J Clin Invest. 1997;99(11):2727–2735.CrossRefGoogle ScholarPubMed
Gardos, G. The function of calcium in the potassium permeability of human erythrocytes. Biochim Biophys Acta. 1958;30:653–654.CrossRefGoogle ScholarPubMed
Hoffman, JF, Joiner, W, Nehrke, K, Potapova, O, Foye, K, Wickrema, A. The hSK4 (KCNN4) isoform is the Ca2+-activated K+ channel (Gardos channel) in human red blood cells. Proc Natl Acad Sci USA. 2003;100(12):7366–7371.CrossRefGoogle Scholar
Vandorpe, DH, Shmukler, BE, Jiang, L, et al. cDNA cloning and functional characterization of the mouse Ca2+-gated K+ channel, mIK1. Roles in regulatory volume decrease and erythroid differentiation. J Biol Chem. 1998;273(34):21542–21553.CrossRefGoogle ScholarPubMed
Ishii, TM, Silvia, C, Hirschberg, B, Bond, CT, Adelman, JP, Maylie, J. A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci USA. 1997;94(21):11651–11656.CrossRefGoogle ScholarPubMed
Heginbotham, L, Lu, Z, Abramson, T, MacKinnon, R. Mutations in the K+ channel signature sequence. Biophys J. 1994;66(4):1061–1067.CrossRefGoogle ScholarPubMed
Wolff, D, Cecchi, X, Spalvins, A, Canessa, M. Charybdotoxin blocks with high affinity the Ca-activated K+ channel of Hb A and Hb S red cells: individual differences in the number of channels. J Membr Biol. 1988;106(3):243–252.CrossRefGoogle ScholarPubMed
Brugnara, C, Armsby, CC, Franceschi, L, Crest, M, Euclaire, MF, Alper, SL. Ca(2+)-activated K+ channels of human and rabbit erythrocytes display distinctive patterns of inhibition by venom peptide toxins. J Membr Biol. 1995;147(1):71–82.CrossRefGoogle ScholarPubMed
Brugnara, C, Franceschi, L, Alper, SL. Ca(2+)-activated K+ transport in erythrocytes. Comparison of binding and transport inhibition by scorpion toxins. J Biol Chem. 1993;268(12):8760–8768.Google ScholarPubMed
Lew, VL, Etzion, Z, Bookchin, RM. Dehydration response of sickle cells to sickling-induced Ca(++) permeabilization. Blood. 2002;99(7):2578–2585.CrossRefGoogle ScholarPubMed
Ohnishi, ST, Katagi, H, Katagi, C. Inhibition of the in vitro formation of dense cells and of irreversibly sickled cells by charybdotoxin, a specific inhibitor of calcium-activated potassium efflux. Biochim Biophys Acta. 1989;1010(2):199–203.CrossRefGoogle ScholarPubMed
Ohnishi, ST, Horiuchi, KY, Horiuchi, K. The mechanism of in vitro formation of irreversibly sickled cells and modes of action of its inhibitors. Biochim Biophys Acta. 1986;886(1):119–129.CrossRefGoogle ScholarPubMed
Horiuchi, K, Asakura, T. Formation of light irreversibly sickled cells during deoxygenation-oxygenation cycles. J Lab Clin Med. 1987;110(5):653–660.Google ScholarPubMed
Franco, RS, Palascak, M, Thompson, H, Rucknagel, DL, Joiner, CH. Dehydration of transferrin receptor-positive sickle reticulocytes during continuous or cyclic deoxygenation: role of KCl cotransport and extracellular calcium. Blood. 1996;88(11):4359–4365.Google ScholarPubMed
McGoron, AJ, Joiner, CH, Palascak, MB, Claussen, WJ, Franco, RS. Dehydration of mature and immature sickle red blood cells during fast oxygenation/deoxygenation cycles: role of KCl cotransport and extracellular calcium. Blood. 2000;95(6):2164–2168.Google ScholarPubMed
Lew, VL, Bookchin, RM. Volume, pH, and ion-content regulation in human red cells: analysis of transient behavior with an integrated model. J Membr Biol. 1986;92(1):57–74.CrossRefGoogle ScholarPubMed
Rivera, A, Rotter, MA, Brugnara, C. Endothelins activate Ca(2+)-gated K(+) channels via endothelin B receptors in CD-1 mouse erythrocytes. Am J Physiol. 1999;277(4 Pt 1):C746–754.CrossRefGoogle ScholarPubMed
Rivera, A, Jarolim, P, Brugnara, C. Modulation of Gardos channel activity by cytokines in sickle erythrocytes. Blood. 2002;99(1):357–603.CrossRefGoogle ScholarPubMed
Li, Q, Jungmann, V, Kiyatkin, A, Low, PS. Prostaglandin E2 stimulates a Ca2+-dependent K+ channel in human erythrocytes and alters cell volume and filterability. J Biol Chem. 1996;271(31):18651–18656.CrossRefGoogle ScholarPubMed
Lang, PA, Kempe, DS, Myssina, S, et al. PGE(2) in the regulation of programmed erythrocyte death. Cell Death Differ. 2005;12(5):415–428.CrossRefGoogle ScholarPubMed
Andrews, DA, Yang, L, Low, PS. Phorbol ester stimulates a protein kinase C-mediated agatoxin-TK-sensitive calcium permeability pathway in human red blood cells. Blood. 2002;100(9):3392–3399.CrossRefGoogle ScholarPubMed
Yang, L, Andrews, DA, Low, PS. Lysophosphatidic acid opens a Ca(++) channel in human erythrocytes. Blood. 2000;95(7):2420–2425.Google Scholar
Werdehoff, SG, Moore, RB, Hoff, CJ, Fillingim, E, Hackman, AM. Elevated plasma endothelin-1 levels in sickle cell anemia: relationships to oxygen saturation and left ventricular hypertrophy. Am J Hematol. 1998;58(3):195–199.3.0.CO;2-M>CrossRefGoogle ScholarPubMed
Graido-Gonzalez E, , Doherty, JC, Bergreen, EW, Organ, G, Telfer, M, McMillen, MA. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood. 1998;92(7):2551–2555.Google ScholarPubMed
Rybicki, AC, Benjamin, LJ. Increased levels of endothelin-1 in plasma of sickle cell anemia patients. Blood. 1998;92(7):2594–2596.Google ScholarPubMed
Hammerman, SI, Kourembanas, S, Conca, TJ, Tucci, M, Brauer, M, Farber, HW. Endothelin-1 production during the acute chest syndrome in sickle cell disease. Am J RespirCrit Care Med. 1997;156(1):280–285.CrossRefGoogle ScholarPubMed
Brugnara, C, Franceschi, L, Alper, SL. Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J Clin Invest. 1993;92(1):520–526.CrossRefGoogle ScholarPubMed
Brugnara, C, Armsby, CC, Sakamoto, M, Rifai, N, Alper, SL, Platt, O. Oral administration of clotrimazole and blockade of human erythrocyte Ca(++)-activated K+ channel: the imidazole ring is not required for inhibitory activity. J Pharmacol Exp Ther. 1995;273(1):266–272.Google Scholar
Lauf, PK, Theg, BE. A chloride dependent K+ flux induced by N-ethylmaleimide in genetically low K+ sheep and goat erythrocytes. Biochem Biophys Res Commun. 1980;92(4):1422–1428.CrossRefGoogle Scholar
Dunham, PB, Stewart, GW, Ellory, JC. Chloride-activated passive potassium transport in human erythrocytes. Proc Natl Acad Sci USA. 1980;77(3):1711–1715.CrossRefGoogle ScholarPubMed
Brugnara, C. Sickle cell disease: from membrane pathophysiology to novel therapies for prevention of erythrocyte dehydration. J Pediatr Hematol Oncol. 2003;25(12):927–933.CrossRefGoogle ScholarPubMed
Adragna, NC, Fulvio, MD, Lauf, PK. Regulation of K-Cl cotransport: from function to genes. [erratum appears in J Membr Biol. 2006 Apr;210(3):213]. J Membr Biol. 2004;201(3):109–137.CrossRefGoogle Scholar
Lauf, PK, Adragna, NC. K-Cl cotransport: properties and molecular mechanism. Cell Physiol Biochem. 2000;10(5–6):341–354.CrossRefGoogle ScholarPubMed
Joiner, CH. Cation transport and volume regulation in sickle red blood cells. Am J Physiol. 1993;264(2 Pt 1):C251–270.CrossRefGoogle ScholarPubMed
Brugnara, C, Tosteson, DC. Cell volume, K transport, and cell density in human erythrocytes. Am J Physiol. 1987;252(3 Pt 1): C269–276.CrossRefGoogle ScholarPubMed
Hall, AC, Ellory, JC. Evidence for the presence of volume-sensitive KCl transport in ‘young’ human red cells. Biochim Biophys Acta. 1986;858(2):317–320.CrossRefGoogle ScholarPubMed
Canessa, M, Fabry, ME, Nagel, RL. Deoxygenation inhibits the volume-stimulated, Cl(-)-dependent K+ efflux in SS and young AA cells: a cytosolic Mg2+ modulation. Blood. 1987;70(6):1861–1866.Google Scholar
Ellory, JC, Hall, AC, Ody, SA. Factors affecting the activation and inactivation of KCl cotransport in ‘young’ human red cells. Biomed Biochim Acta. 1990;49(2–3):S64–69.Google ScholarPubMed
Canessa, M, Spalvins, A, Nagel, RL. Volume-dependent and NEM-stimulated K+,Cl- transport is elevated in oxygenated SS, SC and CC human red cells. FEBS Letters. 1986;200(1):197–202.CrossRefGoogle ScholarPubMed
Brugnara, C, Bunn, HF, Tosteson, DC. Regulation of erythrocyte cation and water content in sickle cell anemia. Science. 1986;232(4748):388–390.CrossRefGoogle ScholarPubMed
Franco, RS, Palascak, M, Thompson, H, Joiner, CH. KCl cotransport activity in light versus dense transferrin receptor-positive sickle reticulocytes. J Clin Invest. 1995;95(6):2573–2580.CrossRefGoogle ScholarPubMed
Joiner, CH, Rettig, RK, Jiang, M, Franco, RS. KCl cotransport mediates abnormal sulfhydryl-dependent volume regulation in sickle reticulocytes. Blood. 2004;104(9):2954–2960.CrossRefGoogle ScholarPubMed
Gibson, XA, Shartava, A, McIntyre, J, et al. The efficacy of reducing agents or antioxidants in blocking the formation of dense cells and irreversibly sickled cells in vitro. Blood. 1998;91(11):4373–4378.Google ScholarPubMed
Pace, BS, Shartava, A, Pack-Mabien A, , Mulekar, M, Ardia, A, Goodman, SR. Effects of N-acetylcysteine on dense cell formation in sickle cell disease. Am J Hematol. 2003;73(1):26–32.CrossRefGoogle ScholarPubMed
Brugnara, C, Ha, T, Tosteson, DC. Acid pH induces formation of dense cells in sickle erythrocytes. Blood. 1989;74(1):487–495.Google ScholarPubMed
Fabry, ME, Romero, JR, Buchanan, ID, et al. Rapid increase in red blood cell density driven by K:Cl cotransport in a subset of sickle cell anemia reticulocytes and discocytes. Blood. 1991;78(1):217–225.Google Scholar
Franco, RS, Thompson, H, Palascak, M, Joiner, CH. The formation of transferrin receptor-positive sickle reticulocytes with intermediate density is not determined by fetal hemoglobin content. Blood. 1997;90(8):3195–3203.Google Scholar
Joiner, CH, Rettig, RK, Jiang, M, Risinger, M, Franco, RS. Urea stimulation of KCl cotransport induces abnormal volume reduction in sickle reticulocytes. [erratum appears in Blood. 2007;109(7):2735]. Blood. 2007;109(4):1728–1735.CrossRefGoogle ScholarPubMed
Joiner, CH, Rettig, RK, Jiang, M, Risinger, M, Franco, RS. Urea stimulation of KCl cotransport induces abnormal volume reduction in sickle reticulocytes. Blood. 2007;109(4):1728–1735.CrossRefGoogle ScholarPubMed
Hebbel, RP, Ney, PA, Foker, W. Autoxidation, dehydration, and adhesivity may be related abnormalities of sickle erythrocytes. Am J Physiol. 1989;256(3 Pt 1):C579–583.CrossRefGoogle ScholarPubMed
Franceschi, L, Beuzard, Y, Brugnara, C. Sulfhydryl oxidation and activation of red cell K(+)-Cl- cotransport in the transgenic SAD mouse. Am J Physiol. 1995;269(4 Pt 1):C899–906.CrossRefGoogle ScholarPubMed
Gibson, JS, Speake, PF, Ellory, JC. Differential oxygen sensitivity of the K+-Cl- cotransporter in normal and sickle human red blood cells. [see comment]. J Physiol. 1998;511(Pt 1):225–234.CrossRefGoogle Scholar
Gibson, JS, Khan, A, Speake, PF, Ellory, JC. O2 dependence of K+ transport in sickle cells: the effect of different cell populations and the substituted benzaldehyde 12C79. FASEB J. 2001;15(3):823–832.CrossRefGoogle ScholarPubMed
Joiner, CH, Franco, RS. The activation of KCL cotransport by deoxygenation and its role in sickle cell dehydration. Blood Cell Mol Dis. 2001;27(1):158–164.CrossRefGoogle ScholarPubMed
Feray, JC, Garay, R. An Na+-stimulated Mg2+-transport system in human red blood cells. Biochim Biophys Acta. 1986;856(1):76–84.CrossRefGoogle ScholarPubMed
Olukoga, AO, Adewoye, HO, Erasmus, RT, Adedoyin, MA. Erythrocyte and plasma magnesium in sickle-cell anaemia. East African Med J. 1990;67(5):348–354.Google ScholarPubMed
Franceschi, L, Villa-Moruzzi E, , Fumagalli, L, et al. K-Cl cotransport modulation by intracellular Mg in erythrocytes from mice bred for low and high Mg levels. Am J Physiol Cell Physiol. 2001;281(4):C1385–1395.CrossRefGoogle ScholarPubMed
Franceschi, L, Brugnara, C, Beuzard, Y. Dietary magnesium supplementation ameliorates anemia in a mouse model of beta-thalassemia. Blood. 1997;90(3):1283–1290.Google Scholar
Franceschi, L, Cappellini, MD, Graziadei, G, et al. The effect of dietary magnesium supplementation on the cellular abnormalities of erythrocytes in patients with beta thalassemia intermedia. Haematologica. 1998;83(2):118–125.Google ScholarPubMed
Franceschi, L, Bachir, D, Galacteros, F, et al. Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest. 1997;100(7):1847–1852.CrossRefGoogle ScholarPubMed
Gamba, G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005;85(2):423–493.CrossRefGoogle ScholarPubMed
Hebert, SC, Mount, DB, Gamba, G. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Eur J Physiol. 2004;447(5):580–593.CrossRefGoogle ScholarPubMed
Haas, M, Forbush, B 3rd. The Na-K-Cl cotransporter of secretory epithelia. Annu Rev Physiol. 2000;62:515–534.CrossRefGoogle ScholarPubMed
Haas, M, Forbush, B 3rd. The Na-K-Cl cotransporters. J Bioenerg Biomembr. 1998;30(2):161–172.CrossRefGoogle ScholarPubMed
Gillen, CM, Brill, S, Payne, JA, Forbush, B 3rd. Molecular cloning and functional expression of the K-Cl cotransporter from rabbit, rat, and human. A new member of the cation-chloride cotransporter family. J Biol Chem. 1996;271(27):16237–16244.CrossRefGoogle Scholar
Payne, JA, Stevenson, TJ, Donaldson, LF. Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform. J Biol Chem. 1996;271(27):16245–16252.CrossRefGoogle Scholar
Song, L, Mercado, A, Vazquez, N, et al. Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter. Brain Res Mol Brain Res. 2002;103(1–2):91–105.CrossRefGoogle ScholarPubMed
Race, JE, Makhlouf, FN, Logue, PJ, Wilson, FH, Dunham, PB, Holtzman, EJ. Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. Am J Physiol. 1999;277(6 Pt 1):C1210–1219.CrossRefGoogle ScholarPubMed
Hiki, K, Andrea, RJ, Furze, J, et al. Cloning, characterization, and chromosomal location of a novel human K+-Cl- cotransporter. J Biol Chem. 1999;274(15):10661–10667.CrossRefGoogle ScholarPubMed
Mount, DB, Mercado, A, Song, L, et al. Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. J Biol Chem. 1999;274(23):16355–16362.CrossRefGoogle ScholarPubMed
Mercado, A, Vazquez, N, Song, L, et al. NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter. Am J Physiol Renal Physiol. 2005;289(6):F1246–1261.CrossRefGoogle ScholarPubMed
Boettger, T, Hubner, CA, Maier, H, Rust, MB, Beck, FX, Jentsch, TJ. Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4. Nature. 2002;416(6883):874–878.CrossRefGoogle ScholarPubMed
Pellegrino, CM, Rybicki, AC, Musto, S, Nagel, RL, Schwartz, RS. Molecular identification and expression of erythroid K:Cl cotransporter in human and mouse erythroleukemic cells. Blood Cell Mol Dis. 1998;24(1):31–40.CrossRefGoogle ScholarPubMed
Lauf, PK, Zhang, J, Delpire, E, Fyffe, RE, Mount, DB, Adragna, NC. K-Cl co-transport: immunocytochemical and functional evidence for more than one KCC isoform in high K and low K sheep erythrocytes. Comp Biochem Physiol. 2001;130(3):499–509.CrossRefGoogle Scholar
Rust, MB, Alper, SL, Rudhard, Y, et al. Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. J Clin Invest. 2007;117(6):1708–1717.CrossRefGoogle ScholarPubMed
Crable, SC, Hammond, SM, Papes, R, et al. Multiple isoforms of the KC1 cotransporter are expressed in sickle and normal erythroid cells. Exp Hematol. 2005;33(6):624–631.CrossRefGoogle ScholarPubMed
Joiner, C, Papes, R, Crable, S, Pan, D, Mount, DB. Functional Comparison of Red Cell KCl Cotransporter isoforms, KCC1, KCC3, and KCC4. Blood. 2006;108:a.Google Scholar
Casula, S, Shmukler, BE, Wilhelm, S, et al. A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity. J Biol Chem. 2001;276(45):41870–41878.CrossRefGoogle Scholar
Plata, C, Mount, DB, Rubio, V, Hebert, SC, Gamba, G. Isoforms of the Na-K-2Cl cotransporter in murine TAL II. Functional characterization and activation by cAMP. Am J Physiol. 1999;276(3 Pt 2):F359–366.Google ScholarPubMed
Gillen, CM, Forbush, B, 3rd. Functional interaction of the K-Cl cotransporter (KCC1) with the Na-K-Cl cotransporter in HEK-293 cells. Am J Physiol. 1999;276(2 Pt 1):C328–336.CrossRefGoogle ScholarPubMed
Piechotta, K, Lu, J, Delpire, E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem. 2002;277(52):50812–50819.CrossRefGoogle Scholar
Garzon-Muvdi T, , Pacheco-Alvarez D, , Gagnon, KB, et al. WNK4 kinase is a negative regulator of K+-Cl- cotransporters. Am J Physiol Renal Physiol. 2007;292(4):F1197–1207.CrossRefGoogle ScholarPubMed
Jennings, ML, Schulz, RK. Swelling-activated KCl cotransport in rabbit red cells: flux is determined mainly by cell volume rather than shape. Am J Physiol. 1990;259(6 Pt 1):C960–967.CrossRefGoogle ScholarPubMed
Jennings, ML, al-Rohil, N. Kinetics of activation and inactivation of swelling-stimulated K+/Cl- transport. The volume-sensitive parameter is the rate constant for inactivation. J Gen Physiol. 1990;95(6):1021–1040.CrossRefGoogle ScholarPubMed
Jennings, ML, Schulz, RK. Okadaic acid inhibition of KCl cotransport. Evidence that protein dephosphorylation is necessary for activation of transport by either cell swelling or N-ethylmaleimide. J Gen Physiol. 1991;97(4):799–817.CrossRefGoogle ScholarPubMed
Kaji, DM, Tsukitani, Y. Role of protein phosphatase in activation of KCl cotransport in human erythrocytes. Am J Physiol. 1991;260(1 Pt 1):C176–180.CrossRefGoogle ScholarPubMed
Colclasure, GC, Parker, JC. Cytosolic protein concentration is the primary volume signal for swelling-induced [K-Cl] cotransport in dog red cells. J Gen Physiol. 1992;100(1):1–10.CrossRefGoogle ScholarPubMed
Parker, JC, Colclasure, GC. Macromolecular crowding and volume perception in dog red cells. Mol Cell Biochem. 1992;114(1–2):9–11.CrossRefGoogle ScholarPubMed
Mallozzi, C, Franceschi, L, Brugnara, C, Di Stasi, AM. Protein phosphatase 1alpha is tyrosine-phosphorylated and inactivated by peroxynitrite in erythrocytes through the src family kinase fgr. Free Radic Biol Med. 2005;38(12):1625–1636.CrossRefGoogle ScholarPubMed
Bize, I, Taher, S, Brugnara, C. Regulation of K-Cl cotransport during reticulocyte maturation and erythrocyte aging in normal and sickle erythrocytes. Am J Physiol Cell Physiol. 2003;285(1):C31–38.CrossRefGoogle ScholarPubMed
Bize, I, Guvenc, B, Buchbinder, G, Brugnara, C. Stimulation of human erythrocyte K-Cl cotransport and protein phosphatase type 2A by n-ethylmaleimide: role of intracellular Mg++. J Membr Biol. 2000;177(2):159–168.CrossRefGoogle ScholarPubMed
Bize, I, Guvenc, B, Robb, A, Buchbinder, G, Brugnara, C. Serine/threonine protein phosphatases and regulation of K-Cl cotransport in human erythrocytes. Am J Physiol. 1999;277(5 Pt 1):C926–936.CrossRefGoogle ScholarPubMed
Lytle, C, Forbush, B 3rd. The Na-K-Cl cotransport protein of shark rectal gland. II. Regulation by direct phosphorylation. J Biol Chem. 1992;267(35):25438–25443.Google ScholarPubMed
Dowd, BF, Forbush, B. PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-Cl cotransporter (NKCC1). J Biol Chem. 2003;278(30):27347–27353.CrossRefGoogle Scholar
Franceschi, L, Fumagalli, L, Olivieri, O, Corrocher, R, Lowell, CA, Berton, G. Deficiency of Src family kinases Fgr and Hck results in activation of erythrocyte K/Cl cotransport. J Clin Invest. 1997;99(2):220–227.CrossRefGoogle ScholarPubMed
Fathallah, H, Coezy, E, Neef, RS, Hardy-Dessources, MD, Giraud, F. Inhibition of deoxygenation-induced membrane protein dephosphorylation and cell dehydration by phorbol esters and okadaic acid in sickle cells. Blood. 1995;86(5):1999–2007.Google ScholarPubMed
Merciris, P, Claussen, WJ, Joiner, CH, Giraud, F. Regulation of K-Cl cotransport by Syk and Src protein tyrosine kinases in deoxygenated sickle cells. Pflugers Archiv – Eur J Physiol. 2003;446(2):232–238.CrossRefGoogle ScholarPubMed
Flatman, PW, Adragna, NC, Lauf, PK. Role of protein kinases in regulating sheep erythrocyte K-Cl cotransport. Am J Physiol. 1996;271(1 Pt 1):C255–263.CrossRefGoogle ScholarPubMed
Bize, I, Dunham, PB. Staurosporine, a protein kinase inhibitor, activates K-Cl cotransport in LK sheep erythrocytes. Am J Physiol. 1994;266(3 Pt 1):C759–770.CrossRefGoogle ScholarPubMed
Franco, RS, Lohmann, J, Silberstein, EB, et al. Time-dependent changes in the density and hemoglobin F content of biotin-labeled sickle cells. J Clin Invest. 1998;101(12):2730–2740.CrossRefGoogle ScholarPubMed
Franco, RS, Yasin, Z, Palascak, MB, Ciraolo, P, Joiner, CH, Rucknagel, DL. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood. 2006;108(3):1073–1076.CrossRefGoogle ScholarPubMed
Dover, GJ, Boyer, SH, Charache, S, Heintzelman, K. Individual variation in the production and survival of F cells in sickle–cell disease. N Engl J Med. 1978;299(26):1428–1435.CrossRefGoogle ScholarPubMed
Reiter, CD, Gladwin, MT. An emerging role for nitric oxide in sickle cell disease vascular homeostasis and therapy. Curr Opin Hematol. 2003;10(2):99–107.CrossRefGoogle ScholarPubMed
Bookchin, R, Tieffert, JT, Daives, SC, Vichinsky, , Lew, VL. Magnesium therapy for sickle cell anemia: a new rationale. In: Beuzard, Y, Lubin, B, Rosa, J, eds. Sickle Cell Disease and Thalasssaemias: New Trends in Therapy. Paris, London: John Libby; 1995.Google Scholar
Rosa, RM, Bierer, BE, Thomas, R, et al. A study of induced hyponatremia in the prevention and treatment of sickle-cell crisis. N Engl J Med. 1980;303(20):1138–1143.CrossRefGoogle ScholarPubMed
Lawrence, C, Fabry, ME, Nagel, RL. The unique red cell heterogeneity of SC disease: crystal formation, dense reticulocytes, and unusual morphology. Blood. 1991;78(8):2104–2112.Google ScholarPubMed
Nagel, RL, Fabry, ME, Steinberg, MH. The paradox of hemoglobin SC disease. Blood Rev. 2003;17(3):167–178.CrossRefGoogle ScholarPubMed
Olivieri, O, Vitoux, D, Galacteros, F, et al. Hemoglobin variants and activity of the (K+Cl-) cotransport system in human erythrocytes. Blood. 1992;79(3):793–797.Google ScholarPubMed
Brugnara, C, Kopin, AS, Bunn, HF, Tosteson, DC. Regulation of cation content and cell volume in hemoglobin erythrocytes from patients with homozygous hemoglobin C disease. J Clin Invest. 1985;75(5):1608–1617.CrossRefGoogle ScholarPubMed
Nagel, RL, Krishnamoorthy, R, Fattoum, S, et al. The erythrocyte effects of haemoglobin O(ARAB). Br J Haematol. 1999;107(3):516–521.CrossRefGoogle Scholar
Olivieri, O, Franceschi, L, Capellini, MD, Girelli, D, Corrocher, R, Brugnara, C. Oxidative damage and erythrocyte membrane transport abnormalities in thalassemias. Blood. 1994;84(1):315–320.Google ScholarPubMed
Franceschi, L, Shalev, O, Piga, A, et al. Deferiprone therapy in homozygous human beta-thalassemia removes erythrocyte membrane free iron and reduces KCl cotransport activity. J Lab Clin Med. 1999;133(1):64–69.CrossRefGoogle ScholarPubMed
Bookchin, RM, Ortiz, OE, Shalev, O, et al. Calcium transport and ultrastructure of red cells in beta-thalassemia intermedia. Blood. 1988;72(5):1602–1607.Google ScholarPubMed
Rhoda, MD, Galacteros, F, Beuzard, Y, Giraud, F. Ca2+ permeability and cytosolic Ca2+ concentration are not impaired in beta-thalassemic and hemoglobin C erythrocytes. Blood. 1987;70(3):804–808.Google Scholar
Franceschi, L, Rouyer-Fessard, P, Alper, SL, Jouault, H, Brugnara, C, Beuzard, Y. Combination therapy of erythropoietin, hydroxyurea, and clotrimazole in a beta thalassemic mouse: a model for human therapy. Blood. 1996;87(3):1188–1195.Google Scholar

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