Skip to main content
SpringerLink
Log in

Inhibition of Cation Channels in Human Erythrocytes by Spermine

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

In erythrocytes, spermine concentration decreases gradually with age, which is paralleled by increases of cytosolic Ca2+ concentration, with subsequent cell shrinkage and cell membrane scrambling. Cytosolic Ca2+ was estimated from Fluo-3 fluorescence, cell volume from forward scatter, cell membrane scrambling from annexin V binding and cation channel activity with whole-cell patch-clamp in human erythrocytes. Extracellular spermine exerted a dual effect on erythrocyte survival. At 200 μM spermine blunted the increase of intracellular Ca2+, cell shrinkage and annexin V binding following 48 h exposure of cells at +37°C. In contrast, short exposure (10–30 min) of cells to 2 mM spermine was accompanied by increased cytosolic Ca2+ and annexin binding. Intracellular addition of spermine at subphysiological concentration (0.2 μM) significantly decreased the conductance of monovalent cations (Na+, K+, NMDG+) and of Ca2+. Moreover, spermine (0.2 μM) blunted the stimulation of voltage-independent cation channels by Cl− removal. Spermine (0.2 and 200 μM) added to the extracellular bath solution similarly inhibited the cation conductance in Cl−-containing bath solution. The effect of 0.2 μM spermine, but not the effect of 200 μM, was rapidly reversible. Acute addition (250 μM) of a naphthyl acetyl derivative of spermine (200 μM) again significantly decreased basal cation conductance in NaCl bath solution and inhibited voltage-independent cation channels. Spermine is a powerful regulator of erythrocyte cation channel cytosolic Ca2+ activity and, thus, cell survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  • Agostinelli E, Tempera G, Viceconte N et al (2010) Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach. Amino Acids 38:353–368

    Article  CAS  PubMed  Google Scholar 

  • Aiken NR, Satterlee JD, Galey WR (1992) Measurement of intracellular Ca2+ in young and old human erythrocytes using 19F-NMR spectroscopy. Biochim Biophys Acta 1136:155–160

    Article  CAS  PubMed  Google Scholar 

  • Bachrach U (1970) Metabolism and function of spermine and related polyamines. Annu Rev Microbiol 24:109–134

    Article  CAS  PubMed  Google Scholar 

  • Bachrach U (1973) Function of naturally occurring polyamines. Academic Press, New York

    Google Scholar 

  • Ballas SK, Clark MR, Mohandas N et al (1983a) Polyamines do not inhibit erythrocyte ATPase activities. Clin Chim Acta 129:287–293

    Article  CAS  PubMed  Google Scholar 

  • Ballas SK, Mohandas N, Marton LJ et al (1983b) Stabilization of erythrocyte membranes by polyamines. Proc Natl Acad Sci USA 80:1942–1946

    Article  CAS  PubMed  Google Scholar 

  • Barry PH, Lynch JW (1991) Liquid junction potentials and small cell effects in patch-clamp analysis. J Membr Biol 121:101–117

    Article  CAS  PubMed  Google Scholar 

  • Baunbaek M, Bennekou P (2008) Evidence for a random entry of Ca2+ into human red cells. Bioelectrochemistry 73:145–150

    Article  CAS  PubMed  Google Scholar 

  • Baylin SB, Rosenstein BJ, Marton LJ et al (1980) Age-related abnormalities of circulating polyamines and diamine oxidase activity in cystic fibrosis heterozygotes and homozygotes. Pediatr Res 14:921–925

    Article  CAS  PubMed  Google Scholar 

  • Bennekou P (1993) The voltage-gated nonselective cation channel from human red cells is sensitive to acetylcholine. Biochim Biophys Acta 1147:165–167

    Article  CAS  PubMed  Google Scholar 

  • Bennekou P, Barksmann TL, Jensen LR et al (2004) Voltage activation and hysteresis of the nonselective voltage-dependent channel in the intact human red cell. Bioelectrochemistry 62:181–185

    Article  CAS  PubMed  Google Scholar 

  • Bordin L, Cattapan F, Clari G et al (1994) Spermine-mediated casein kinase II-uptake by rat liver mitochondria. Biochim Biophys Acta 1199:266–270

    CAS  PubMed  Google Scholar 

  • Bosman GJ, Willekens FL, Werre JM (2005) Erythrocyte aging: a more than superficial resemblance to apoptosis? Cell Physiol Biochem 16:1–8

    Article  CAS  PubMed  Google Scholar 

  • Brand V, Koka S, Lang C et al (2008) Influence of amitriptyline on eryptosis, parasitemia and survival of Plasmodium berghei-infected mice. Cell Physiol Biochem 22:405–412

    Article  CAS  PubMed  Google Scholar 

  • Browning JA, Staines HM, Robinson HC et al (2007) The effect of deoxygenation on whole-cell conductance of red blood cells from healthy individuals and patients with sickle cell disease. Blood 109:2622–2629

    Article  CAS  PubMed  Google Scholar 

  • Bucki R, Bachelot-Loza C, Zachowski A et al (1998) Calcium induces phospholipid redistribution and microvesicle release in human erythrocyte membranes by independent pathways. Biochemistry 37:15383–15391

    Article  CAS  PubMed  Google Scholar 

  • Cala PM, Norby JG, Tosteson DC (1982) Effects of the plant alkaloid sanguinarine on cation transport by human red blood cells and lipid bilayer membranes. J Membr Biol 64:23–31

    Article  CAS  PubMed  Google Scholar 

  • Cino I, Formenti A (2008) Spermine biphasically affects N-type calcium channel currents in adult dorsal root ganglion neurons of the rat. Biochim Biophys Acta 1778:2437–2443

    Article  CAS  PubMed  Google Scholar 

  • Clari G, Toninello A, Bordin L et al (1994) Spermine effect on the binding of casein kinase I to the rat liver mitochondrial structures. Biochem Biophys Res Commun 205:389–395

    Article  CAS  PubMed  Google Scholar 

  • Cohen LF, Lundgren DW, Farrell PM (1976) Distribution of spermidine and spermine in blood from cystic fibrosis patients and control subjects. Blood 48:469–475

    CAS  PubMed  Google Scholar 

  • Cooper KD, Shukla JB, Rennert OM (1976) Polyamine distribution in cellular compartments of blood and in aging erythrocytes. Clin Chim Acta 73:71–88

    Article  CAS  PubMed  Google Scholar 

  • Corry B, Allen TW, Kuyucak S et al (2001) Mechanisms of permeation and selectivity in calcium channels. Biophys J 80:195–214

    Article  CAS  PubMed  Google Scholar 

  • Dalla VL, Di NV, Siliprandi D et al (1996) Spermine binding to liver mitochondria. Biochim Biophys Acta 1284:247–252

    Article  Google Scholar 

  • Dalla VL, Di NV, Toninello A (1998) Spermine binding to liver mitochondria deenergized by ruthenium red plus either FCCP or antimycin A. FEBS Lett 422:36–42

    Article  Google Scholar 

  • Duranton C, Huber SM, Lang F (2002) Oxidation induces a Cl−-dependent cation conductance in human red blood cells. J Physiol 539:847–855

    Article  CAS  PubMed  Google Scholar 

  • Egee S, Mignen O, Harvey BJ et al (1998) Chloride and nonselective cation channels in unstimulated trout red blood cells. J Physiol 511(Pt 1):213–224

    Article  CAS  PubMed  Google Scholar 

  • Estevez AY, Strange K (2005) Calcium feedback mechanisms regulate oscillatory activity of a TRP-like Ca2+ conductance in C. elegans intestinal cells. J Physiol 567:239–251

    Article  CAS  PubMed  Google Scholar 

  • Ferrante A, Rzepczyk CM, Allison AC (1983) Polyamine oxidase mediates intra-erythrocytic death of Plasmodium falciparum. Trans R Soc Trop Med Hyg 77:789–791

    Article  CAS  PubMed  Google Scholar 

  • Foller M, Kasinathan RS, Koka S et al (2008) TRPC6 contributes to the Ca2+ leak of human erythrocytes. Cell Physiol Biochem 21:183–192

    Article  PubMed  Google Scholar 

  • Foller M, Bobbala D, Koka S et al (2009a) Suicide for survival—death of infected erythrocytes as a host mechanism to survive malaria. Cell Physiol Biochem 24:133–140

    Article  PubMed  Google Scholar 

  • Foller M, Mahmud H, Gu S et al (2009b) Modulation of suicidal erythrocyte cation channels by an AMPA antagonist. J Cell Mol Med 13:3680–3686

    Article  PubMed  Google Scholar 

  • Foller M, Bobbala D, Koka S et al (2010) Functional significance of the intermediate conductance Ca2+-activated K+ channel for the short-term survival of injured erythrocytes. Pflugers Arch 460:1029

    Article  PubMed  Google Scholar 

  • Huber SM, Gamper N, Lang F (2001) Chloride conductance and volume-regulatory nonselective cation conductance in human red blood cell ghosts. Pflugers Arch 441:551–558

    Article  CAS  PubMed  Google Scholar 

  • Hughes G, Starling AP, East JM et al (1994) Mechanism of inhibition of the Ca2+-ATPase by spermine and other polycationic compounds. Biochemistry 33:4745–4754

    Article  CAS  PubMed  Google Scholar 

  • Kaestner L, Bernhardt I (2002) Ion channels in the human red blood cell membrane: their further investigation and physiological relevance. Bioelectrochemistry 55:71–74

    Article  CAS  PubMed  Google Scholar 

  • Kaestner L, Bollensdorff C, Bernhardt I (1999) Nonselective voltage-activated cation channel in the human red blood cell membrane. Biochim Biophys Acta 1417:9–15

    Article  CAS  PubMed  Google Scholar 

  • Kaestner L, Christophersen P, Bernhardt I et al (2000) The nonselective voltage-activated cation channel in the human red blood cell membrane: reconciliation between two conflicting reports and further characterisation. Bioelectrochemistry 52:117–125

    Article  CAS  PubMed  Google Scholar 

  • Kempe DS, Lang PA, Duranton C et al (2006) Enhanced programmed cell death of iron-deficient erythrocytes. FASEB J 20:368–370

    CAS  PubMed  Google Scholar 

  • Kempe DS, Akel A, Lang PA et al (2007) Suicidal erythrocyte death in sepsis. J Mol Med 85:273–281

    Article  CAS  PubMed  Google Scholar 

  • Kerschbaum HH, Kozak JA, Cahalan MD (2003) Polyvalent cations as permeant probes of MIC and TRPM7 pores. Biophys J 84:2293–2305

    Article  CAS  PubMed  Google Scholar 

  • Khan NA, Quemener V, Moulinoux P (1990) Inhibition of adenylate cyclase activity by polyamines in human erythrocyte plasma membranes. Life Sci 46:43–47

    Article  CAS  PubMed  Google Scholar 

  • Kiefer CR, Snyder LM (2000) Oxidation and erythrocyte senescence. Curr Opin Hematol 7:113–116

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi M, Fujisaki H, Sugawara M et al (1999) The presence of an Na+/spermine antiporter in the rat renal brush-border membrane. J Pharm Pharmacol 51:279–284

    Article  CAS  PubMed  Google Scholar 

  • Koenig H, Goldstone A, Lu CY (1983) Polyamines regulate calcium fluxes in a rapid plasma membrane response. Nature 305:530–534

    Article  CAS  PubMed  Google Scholar 

  • Koike M, Iino M, Ozawa S (1997) Blocking effect of 1-naphthyl acetyl spermine on Ca2+-permeable AMPA receptors in cultured rat hippocampal neurons. Neurosci Res 29:27–36

    Article  CAS  PubMed  Google Scholar 

  • Koka S, Lang C, Boini KM et al (2008a) Influence of chlorpromazine on eryptosis, parasitemia and survival of Plasmodium berghe infected mice. Cell Physiol Biochem 22:261–268

    Article  CAS  PubMed  Google Scholar 

  • Koka S, Lang C, Niemoeller OM et al (2008b) Influence of NO synthase inhibitor l-NAME on parasitemia and survival of Plasmodium berghei infected mice. Cell Physiol Biochem 21:481–488

    Article  CAS  PubMed  Google Scholar 

  • Koka S, Bobbala D, Lang C et al (2009) Influence of paclitaxel on parasitemia and survival of Plasmodium berghei infected mice. Cell Physiol Biochem 23:191–198

    Article  CAS  PubMed  Google Scholar 

  • Kossorotow A, Wolf HU, Seiler N (1974) Regulatory effects of polyamines on membrane-bound acetylcholinesterase. Biochem J 144:21–27

    CAS  PubMed  Google Scholar 

  • Kucherenko Y, Bhavsar SK, Grischenko VI et al (2010) Increased cation conductance in human erythrocytes artificially aged by glycation. J Membr Biol 235:177

    Article  CAS  PubMed  Google Scholar 

  • Kuypers FA (2007) Membrane lipid alterations in hemoglobinopathies. Hematology Am Soc Hematol Educ Program 2007:68–73

    Google Scholar 

  • Lang PA, Beringer O, Nicolay JP et al (2006) Suicidal death of erythrocytes in recurrent hemolytic uremic syndrome. J Mol Med 84:378–388

    Article  PubMed  Google Scholar 

  • Lang PA, Schenck M, Nicolay JP et al (2007) Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med 13:164–170

    Article  CAS  PubMed  Google Scholar 

  • Lang F, Gulbins E, Lerche H et al (2008) Eryptosis, a window to systemic disease. Cell Physiol Biochem 22:373–380

    Article  CAS  PubMed  Google Scholar 

  • Lang PA, Kasinathan RS, Brand VB et al (2009) Accelerated clearance of Plasmodium-infected erythrocytes in sickle cell trait and Annexin-A7 deficiency. Cell Physiol Biochem 24:415–428

    Article  CAS  PubMed  Google Scholar 

  • Lapaix F, Bouyer G, Thomas S et al (2008) Further characterization of cation channels present in the chicken red blood cell membrane. Bioelectrochemistry 73:129–136

    Article  CAS  PubMed  Google Scholar 

  • Lenzen S, Munster W, Rustenbeck I (1992) Dual effect of spermine on mitochondrial Ca2+ transport. Biochem J 286(Pt 2):597–602

    CAS  PubMed  Google Scholar 

  • Lew VL, Daw N, Etzion Z et al (2007) Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells. Blood 110:1334–1342

    Article  CAS  PubMed  Google Scholar 

  • Lin X, Fenn E, Veenstra RD (2006) An amino-terminal lysine residue of rat connexin40 that is required for spermine block. J Physiol 570:251–269

    CAS  PubMed  Google Scholar 

  • Lui JC, Wong JW, Suen YK et al (2007) Cordycepin induced eryptosis in mouse erythrocytes through a Ca2+-dependent pathway without caspase-3 activation. Arch Toxicol 81:859–865

    Article  CAS  PubMed  Google Scholar 

  • Mahmud H, Mauro D, Qadri SM et al (2009) Triggering of suicidal erythrocyte death by amphotericin B. Cell Physiol Biochem 24:263–270

    Article  CAS  PubMed  Google Scholar 

  • Makhro A, Wang J, Vogel J et al (2010) Functional NMDA receptors in rat erythrocytes. Am J Physiol Cell Physiol 298:C1315–C1325

    Article  CAS  PubMed  Google Scholar 

  • Molgo J, del Pozo E, Banos JE et al (1991) Changes of quantal transmitter release caused by gadolinium ions at the frog neuromuscular junction. Br J Pharmacol 104:133–138

    CAS  PubMed  Google Scholar 

  • Niemoeller OM, Foller M, Lang C et al (2008a) Retinoic acid induced suicidal erythrocyte death. Cell Physiol Biochem 21:193–202

    Article  CAS  PubMed  Google Scholar 

  • Niemoeller OM, Mahmud H, Foller M et al (2008b) Ciglitazone and 15d-PGJ2 induced suicidal erythrocyte death. Cell Physiol Biochem 22:237–244

    Article  CAS  PubMed  Google Scholar 

  • Nilius B, Prenen J, Voets T et al (2004) Intracellular nucleotides and polyamines inhibit the Ca2+-activated cation channel TRPM4b. Pflugers Arch 448:70–75

    Article  CAS  PubMed  Google Scholar 

  • Orta M, Ordoqui E, Aranzabal A et al (2003) Anaphylactic reaction after artificial insemination. Ann Allergy Asthma Immunol 90:446–451

    Article  PubMed  Google Scholar 

  • Proctor MS, Fletcher HV Jr, Shukla JB et al (1975) Elevated spermidine and spermine levels in the blood of psoriasis patients. J Invest Dermatol 65:409–411

    Article  CAS  PubMed  Google Scholar 

  • Rennert O, Miale T, Shukla J et al (1976) Polyamine concentrations in bone marrow aspirates of children with leukemia and other malignancies. Blood 47:695–701

    CAS  PubMed  Google Scholar 

  • Romero PJ, Romero EA, Mateu D et al (2006) Voltage-dependent calcium channels in young and old human red cells. Cell Biochem Biophys 46:265–276

    Article  CAS  PubMed  Google Scholar 

  • Russell DH (1971) Increased polyamine concentrations in the urine of human cancer patients. Nat New Biol 233:144–145

    CAS  PubMed  Google Scholar 

  • Rzepczyk CM, Saul AJ, Ferrante A (1984) Polyamine oxidase-mediated intraerythrocytic killing of Plasmodium falciparum: evidence against the role of reactive oxygen metabolites. Infect Immun 43:238–244

    CAS  PubMed  Google Scholar 

  • Sachs JR (1994) Soluble polycations and cationic amphiphiles inhibit volume-sensitive K-Cl cotransport in human red cell ghosts. Am J Physiol Cell Physiol 266:C997–C1005

    CAS  Google Scholar 

  • Sanchez-Chapula JA, Sanguinetti MC (2000) Altered gating of HERG potassium channels by cobalt and lanthanum. Pflugers Arch 440:264–274

    CAS  PubMed  Google Scholar 

  • Shaw GG (1994) Polyamines as neurotransmitters or modulators. In: Carter C (ed) Neuropharmacology of polyamines. Academic Press, London, pp 61–80

    Google Scholar 

  • Shi J, Mori E, Mori Y et al (2004) Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cells. J Physiol 561:415–432

    Article  CAS  PubMed  Google Scholar 

  • Sopjani M, Foller M, Dreischer P et al (2008a) Stimulation of eryptosis by cadmium ions. Cell Physiol Biochem 22:245–252

    Article  CAS  PubMed  Google Scholar 

  • Sopjani M, Foller M, Gulbins E et al (2008b) Suicidal death of erythrocytes due to selenium-compounds. Cell Physiol Biochem 22:387–394

    Article  CAS  PubMed  Google Scholar 

  • Starushchenko AV, Neguliaev I, Morachevskaia EZ (2002) Inhibiting and stimulating effect of amiloride on potential-dependent cation channels in K562 cells [in Russian]. Tsitologiia 44:676–680

    CAS  PubMed  Google Scholar 

  • Tassoni A, Antognoni F, Bagni N (1996) Polyamine binding to plasma membrane vesicles isolated from zucchini hypocotyls. Plant Physiol 110:817–824

    CAS  PubMed  Google Scholar 

  • Toner M, Vaio G, McLaughlin A et al (1988) Adsorption of cations to phosphatidylinositol 4,5-bisphosphate. Biochemistry 27:7435–7443

    Article  CAS  PubMed  Google Scholar 

  • Ullrich ND, Voets T, Prenen J et al (2005) Comparison of functional properties of the Ca2+-activated cation channels TRPM4 and TRPM5 from mice. Cell Calcium 37:267–278

    Article  CAS  PubMed  Google Scholar 

  • Vandorpe DH, Xu C, Shmukler BE et al (2010) Hypoxia activates a Ca2+-permeable cation conductance sensitive to carbon monoxide and to GsMTx-4 in human and mouse sickle erythrocytes. PLoS One 5:e8732

    Article  PubMed  Google Scholar 

  • Wang K, Mahmud H, Foller M et al (2008) Lipopeptides in the triggering of erythrocyte cell membrane scrambling. Cell Physiol Biochem 22:381–386

    Article  CAS  PubMed  Google Scholar 

  • Zhu S, Ashok M, Li J et al (2009) Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers. Mol Med 15:275–282

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the meticulous preparation of the manuscript by Lejla Subasic and Tanja Loch. This study was supported by the Deutsche Forschungsgemeinschaft (La 315/13-3).

Author information

Authors and Affiliations

  1. Department of Physiology Institute I, Eberhard-Karls Universität Tübingen, 72076, Tübingen, Germany

    Yuliya V. Kucherenko & Florian Lang

  2. Institute for Problems of Cryobiology and Cryomedicine, Ukrainian National Academy of Sciences, Kharkov, 61015, Ukraine

    Yuliya V. Kucherenko

Authors
  1. Yuliya V. Kucherenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florian Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Florian Lang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kucherenko, Y.V., Lang, F. Inhibition of Cation Channels in Human Erythrocytes by Spermine. J Membrane Biol 237, 93–106 (2010). https://doi.org/10.1007/s00232-010-9310-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-010-9310-1

Keywords

Search

Navigation