¹ Institute for Problems of Cryobiology and Cryomedicine, National Academy of Sciences of the Ukraine, Kharkov, Ukraine
² National University of Pharmacy, Kharkov, Ukraine
*Corresponding author: Sergey V. Rudenko, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Sciences of the Ukraine. 23 Pereyaslavskaya Str. 23, 61015, Kharkov, Ukraine. Tel.: +38 057 373-4143; Fax: +38 057 373-3084; e-mail: rsv@kharkov.ua
Published: June 25, 2013
Human red blood cells (RBCs) when suspended in a Low Ionic Strength medium (LIS) demonstrate characteristic triphasic shape changes (morphological response, MR) and become reduced in volume. Tahitian Tabari Noni juice (Tb), after being given during the terminal phase of MR, was shown to initiate an unusual cell response. This response can be described as a volumetric four-phasic response including first a shrinking phase, attributed to the initial sucrose-induced shrinkage during typical MR, a rapid first swelling phase, induced by application of the juice, followed spontaneously by the occurrence of a more prolonged second shrinking phase, which culminated in the swelling and hemolysis of the cells. All the phases of volumetric response can be independently regulated by chloride, DIDS, cations Ca2+, Ag+, Hg2+ or plasma. The second shrinking phase is not inhibited by clotrimazole, a known inhibitor of Gardos channels, and can be replicated by a mixture of two ionophores (valinomycin and CCCP), suggesting the involvement of the putative K+/H+ exchanger as a mechanism of this phase. We suggest that the erythrocyte membrane is equipped with additional molecular systems, poorly characterized at present, that regulate the cell shape and volume. The cell should, therefore, be considered as an “active” responsive system instead of a “passive” osmometer-like structure.
1. Lew VL, Raftos JE, Sorette M, Bookchin RM, Mohandas N. Generation of normal human red cell volume, hemoglobin content, and membrane area distributions by "birth" or regulation? Blood 1995; 86:334-41.
2. 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; 68:506-13.
3. Martinov MV, Vitvitsky VM, Ataullakhanov FI. Volume stabilization in human erythrocytes: combined effects of Ca2+-dependent potassium channels and adenylate metabolism. Biophys Chem 1999; 80(3):199-215.
4. Bennekou P, Kristensen BI, Christophersen P. The human red cell voltage-regulated cation channel. The interplay with the chloride conductance, the Ca(2+)-activated K(+) channel and the Ca(2+) pump. J Membr Biol 2003; 195(1):1-8.
5. Koivusalo M, Kapus A, Grinstein S. Sensors, transducers, and effectors that regulate cell size and shape. J Biol Chem 2009; 284(11):6595-6599.
6. O'Neill WC. Physiological significance of volume-regulatory transporters. Am J Physiol 1999; 276(5 Pt 1):C995-C1011.
7. Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D. Functional significance of cell volume regulatory mechanisms. Physiol Rev 1998; 78(1):247-306.
8. Lang F, Gulbins E, Szabo I, Lepple-Wienhues A, Huber SM, Duranton C, Lang KS, Lang PA, Wieder T. Cell volume and the regulation of apoptotic cell death. J Mol Recognit 2004; 17(5):473-80.
9. Al-Habori M. Macromolecular crowding and its role as intracellular signalling of cell volume regulation. Int J Biochem Cell Biol 2001; 33(9):844-64.
10. Parker JC, Colclasure GC. Macromolecular crowding and volume perception in dog red cells. Mol Cell Biochem 1992; 114(1-2):9-11.
11. Parker JC. In defense of cell volume? Am J Physiol 1993; 265(5 Pt 1):C1191-C200.
12. Garner MM, Burg MB. Macromolecular crowding and confinement in cells exposed to hypertonicity. Am J Physiol 1994; 266(4 Pt 1):C877-C92.
13. Heubusch P, Jung CY, Green FA. The osmotic response of human erythrocytes and the membrane cytoskeleton. J Cell Physiol 1985; 122(2):266-72.
14. Lauf PK, Adragna NC. Functional evidence for a pH sensor of erythrocyte K-Cl cotransport through inhibition by internal protons and diethylpyrocarbonate. Cell Physiol Biochem 1998; 8(1-2):46-60.
15. O'Neill WC. Cl-dependent K transport in a pure population of volume-regulating human erythrocytes. Am J Physiol 1989; 256(4 Pt 1):C858-C64.
16. Quarmyne MO, Risinger M, Linkugel A, Frazier A, Joiner C. Volume regulation and KCl cotransport in reticulocyte populations of sickle and normal red blood cells. Blood Cells Mol Dis 2011; 47(2):95-9.
17. Brugnara C. Erythrocyte membrane transport physiology. Curr Opin Hematol 1997; 4(2):122-7.
18. Boron WF. Regulation of intracellular pH. Adv Physiol Educ 2004; 28(1-4):160-79.
19. Swietach P, Tiffert T, Mauritz JM, Seear R, Esposito A, Kaminski CF, Lew VL, Vaughan-Jones RD. Hydrogen ion dynamics in human red blood cells. J Physiol 2010; 588(pt 24):4995-5014.
20. Potterat O, Felten RV, Dalsgaard PW, Hamburger M. Identification of TLC markers and quantification by HPLC-MS of various constituents in noni fruit powder and commercial noni-derived products. J Agric Food Chem 2007; 55(18):7489-94.
21. Wang MY, Su C. Cancer preventive effect of Morinda citrifolia (Noni). Ann N Y Acad Sci 2001; 952:161-8.
22. Wang MY, Nowicki D, Anderson G, Jensen J, West B. Liver protective effects of Morinda citrifolia (Noni). Plant Foods Hum Nutr 2008; 63(2):59-63.
23. Palu AK, Kim AH, West BJ, Deng S, Jensen J, White L. The effects of Morinda citrifolia L. (noni) on the immune system: its molecular mechanisms of action. J Ethnopharmacol 2008; 115(3):502-6.
24. Rudenko SV. Characterization of morphological response of red cells in a sucrose solution. Blood Cells Mol Dis 2009; 42(3):252-61.
25. Rudenko SV, Crowe JH, Tablin F. Determination of time-dependent shape changes in red blood cells. Biochemistry (Mosc ) 1998; 63(12):1385-94.
26. Rudenko SV. Erythrocyte morphological states, phases, transitions and trajectories. Biochim Biophys Acta 2010; 1798(9):1767-78.
27. Rudenko SV, Zupanets IA. Shape and volume restoring phenomena in human erythrocyte suspension under low ion strength conditions. Int J Biomedicine 2013; 3:32-40.
28. Hoffman JF. On the mechanism and measurement of shape transformations of constant volume of human red blood cells. Blood Cells 1987; 12(3):565-88.
29. Yang B, Kim JK, Verkman AS. Comparative efficacy of HgCl2 with candidate aquaporin-1 inhibitors DMSO, gold, TEA+ and acetazolamide. FEBS Lett 2006; 580(28-29):6679-84.
30. Bennekou P, Barksmann TL, Jensen LR, Kristensen BI, Christophersen P. Voltage activation and hysteresis of the non-selective voltage-dependent channel in the intact human red cell. Bioelectrochemistry 2004; 62(2):181-5.
31. 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.
32. Ponder E. Hemolysis and related phenomena. New York: Grune and Stratton, Inc; 1948.
33. Cook JS. Nonsolvent water in human erythrocytes. J Gen Physiol 1967; 50(5):1311-25.
34. LeFevre PG. The osmotically functional water content of the human erythrocyte. J Gen Physiol 1964; 47:585-603.
35. Fullerton GD, Kanal KM, Cameron IL. On the osmotically unresponsive water compartment in cells. Cell Biol Int 2006; 30(1):74-7.
36. Olmstead EG. Efflux and influx of erythrocyte water. J Gen Physiol 1960; 44:227-33.
37. Olmstead EG. Efflux of red cell water into buffered hypertonic solutions. J Gen Physiol 1960; 43:707-12.
38. Olmstead EG. Extracellular and metabolic factors affecting the efflux and influx of erythrocyte water. J Gen Physiol 1961; 45:59-68.
39. Rudenko SV, Budilova JV. Peculiarities of the osmotic response in dehydrated erythrocytes. Membr Cell Biol 1997; 10(6):613-21.
40. Rudenko SV, Peresetskaia NM. [Anomalous transport of cations upon stimulation of a Ca-dependent K-channel in rehydrated erythrocytes]. Biokhimiia 1995; 60(7):1146-54. [Article in Russian].
41. Bisognano JD, Dix JA, Pratap PR, Novak TS, Freedman JC. Proton (or hydroxide) fluxes and the biphasic osmotic response of human red blood cells. J Gen Physiol 1993; 102(1):99-123.
42. Freedman JC, Hoffman JF. Ionic and osmotic equilibria of human red blood cells treated with nystatin. J Gen Physiol 1979; 74(2):157-85.
43. Glaser R, Fujii T, Muller P, Tamura E, Herrmann A. Erythrocyte shape dynamics: influence of electrolyte conditions and membrane potential. Biomed Biochim Acta 1987; 46(2-3):S327-33.
44. Hartmann J, Glaser R. The influence of chlorpromazine on the potential-induced shape change of human erythrocyte. Biosci Rep 1991; 11(4):213-21.
45. Muller P, Herrmann A, Glaser R. Further evidence for a membrane potential-dependent shape transformation of the human erythrocyte membrane. Biosci Rep 1986; 6(11):999-1006.
46. Nwafor A, Coakley WT. Drug-induced shape change in erythrocytes correlates with membrane potential change and is independent of glycocalyx charge. Biochem Pharmacol 1985; 34(18):3329-36.
47. Nwafor A, Coakley WT. Charge-independent effects of drugs on erythrocyte morphology. Biochem Pharmacol 1986; 35(6):953-57.
48. Jacobs MH, Stewart DR. Osmotic properties of the erythrocyte; ionic and osmotic equilibria with a complex external solution. J Cell Physiol 1947; 30(1):79-103.
49. Lahajnar G, Pecar S, Sepe A. Na-nitroprusside and HgCl2 modify the water permeability and volume of human erythrocytes. Bioelectrochemistry 2007; 70(2):462-8.
50. Dise CA, Goodman DB. The relationship between valinomycin-induced alterations in membrane phospholipid fatty acid turnover, membrane potential, and cell volume in the human erythrocyte. J Biol Chem 1985; 260(5):2869-74.
51. Skals M, Jensen UB, Ousingsawat J, Kunzelmann K, Leipziger J, Praetorius HA. Escherichia coli alpha-hemolysin triggers shrinkage of erythrocytes via K(Ca)3.1 and TMEM16A channels with subsequent phosphatidylserine exposure. J Biol Chem 2010; 285(20):15557-65.
52. Barksmann TL, Kristensen BI, Christophersen P, Bennekou P. Pharmacology of the human red cell voltage-dependent cation channel; Part I. Activation by clotrimazole and analogues. Blood Cells Mol Dis 2004; 32(3):384-8.
53. Bernhardt I, Bogdanova AY, Kummerow D, Kiessling K, Hamann J, Ellory JC. Characterization of the K+ (Na+)/H+ monovalent cation exchanger in the human red blood cell membrane: effects of transport inhibitors. Gen Physiol Biophys 1999; 18(2):119-37.
54. Bernhardt I, Kummerow D, Weiss E. K+(Na+)/H+ exchange in human erythrocytes activated under low ionic strength conditions. Blood Cells Mol Dis 2001; 27(1):108-11.
55. Kummerow D, Hamann J, Browning JA, Wilkins R, Ellory JC, Bernhardt I. Variations of intracellular pH in human erythrocytes via K(+)(Na(+))/H(+) exchange under low ionic strength conditions. J Membr Biol 2000; 176(3):207-16.
56. Bernhardt I, Weiss E, Robinson HC, Wilkins R, Bennekou P. Differential effect of HOE642 on two separate monovalent cation transporters in the human red cell membrane. Cell Physiol Biochem 2007; 20(5):601-6.
57. Wrobel A. Effects of charged amphiphiles in depolarising solutions on potassium efflux and the osmotic fragility of human erythrocytes. Bioelectrochemistry 2008; 73(2):117-22.
58. Engstrom KG, Meiselman HJ. Combined use of micropipette aspiration and perifusion for studying red blood cell volume regulation. Cytometry 1997; 27(4):345-52.
59. Pafundo DE, Alvarez CL, Krumschnabel G, Schwarzbaum PJ. A volume regulatory response can be triggered by nucleosides in human erythrocytes, a perfect osmometer no longer. J Biol Chem 2010; 285(9):6134-44.
The fully formatted PDF version is available.
Int J Biomed. 2013; 3(2):104-111. © 2013 International Medical Research and Development Corporation. All rights reserved.
