Skip to main content
SpringerLink
Log in

The role of ion transport in the regulation of cell proliferation

  • Proceedings of the Third International Workshop on Developmental Renal Physiology September 6–7, 1986 Tokyo, Japan
  • Review Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The stimulation of growth in a variety of cell types is followed by rapid changes in ion transport across the plasma membrane and in the intracellular concentration of various ions. The addition of various growth factors to fibroblasts, for example, causes stimulation of Na+ entry through the Na+−H+ antiport. This results in the alkalinization of the cytosol and an increase in intracellular Na+ concentration. The increased intracellular Na+ in turn stimulates the Na+/K+ pump, raising the concentration of K+ and lowering the Na+ toward normal. These changes in monovalent ion transport appear to be a necessary part of the proliferative response. In addition to the changes in cytosolic Na+, K+, and pH, a number of growth factors also cause a rapid increase in the cytosolic concentration of Ca2+. The additional Ca2+ appears to come from intracellular organelles, since the effect does not require Ca2+ in the extracellular medium. The change in intracellular Ca2+ concentration persists for only a few minutes. Changes in ion transport have been observed after the addition of mitogens to a variety of cell types, including epithelial cells. For example, we have found that stimulation of proliferation of MDCK (dog kidney epithelial) cells by either serum or vasopressin is followed by stimulation of the activity of the Na+/K+ pump. The manner in which these rapid changes in ion transport may play a role in signalling the onset of the mitogenic response will be discussed.

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

Similar content being viewed by others

References

  1. Rozengurt E, Mendoza SA (1985) Synergistic signals in mitogenesis: role of ion fluxes, cyclic nucleotides and protein kinase C in Swiss 3T3 cells. J Cell Sci [Suppl] 3: 229–242

    Google Scholar 

  2. Rozengurt E, Mendoza SA (1986) Early stimulation of Na+−H+ antiport, Na+−K+ pump activity, and Ca2+ fluxes in fibroblast mitogenesis. Curr Top Membr Trans 27: 163–191

    Google Scholar 

  3. Mendoza SA, Lopez-Rivas A, Sinnett-Smith JW, Rozengurt E (1986) Phorbol esters and diacylglycerol inhibit vasopressin-stimulated increases in cytoplasmic-free Ca2+ and45Ca2+ efflux in Swiss 3T3 cells. Exp Cell Res 164: 536–545

    Google Scholar 

  4. Rozengurt E, Heppel LA (1975) Serum rapidly stimulates ouabain-sensitive86Rb uptake in 3T3 cells. Proc Natl Acad Sci USA 72: 4492–4495

    Google Scholar 

  5. Mendoza SA, Wigglesworth NM, Pohjanpelto P, Rozengurt E (1980) Na entry and Na−K pump activity in murine, hamster and human cells. Effect of monensin, serum, platelet extract and viral transformation. J Cell Physiol 103: 17–27

    Google Scholar 

  6. Grinstein S, Rothstein A (1986) Mechanisms of regulation of the Na+/H+ exchanger. J Membr Biol 90: 1–12

    Google Scholar 

  7. Seifter JL, Aronson PS (1986) Properties and physiologic roles of the plasma membrane sodium-hydrogen exchanger. J Clin Invest 78: 859–864

    Google Scholar 

  8. Schuldiner S, Rozengurt E (1982) Na+/H+ antiport in Swiss 3T3 cells: mitogenic stimulation leads to cytoplasmic alkalinization. Proc Natl Acad Sci USA 79: 7778–7782

    Google Scholar 

  9. Burns CP, Rozengurt E (1983) Serum, platelet-derived growth factor, vasopresin and phorbol esters increase intracellular pH in Swiss 3T3 cells. Biochem Biophys Res Commun 116: 931–938

    Google Scholar 

  10. Mendoza SA, Schneider JA, Lopez-Rivas A, Sinnett-Smith JW, Rozengurt E (1986) Early events elicited by bombesin and structurally related peptides in quiescent Swiss 3T3 cells. II. Changes in Na+ and Ca2+ fluxes, Na+/K+ pump activity and intracellular pH. J Cell Biol 102: 2223–2233

    Google Scholar 

  11. Pouysségur J, Sardet C, Franchi A, L'Allemain G, Paris S (1984) A specific mutation abolishing Na+/H+ antiport activity in hamster fibroblasts precludes growth at neutral and acidic pH. Proc Natl Acad Sci USA 81: 4833–4837

    Google Scholar 

  12. Pouysségur J, Franchi A, L'Allemain G, Paris S (1985) Cytoplasmic pH, a key determinant of growth factor-induced DNA synthesis in quiescent fibroblasts. FEBS Lett 190: 115–119

    Google Scholar 

  13. L'Allemain G, Paris S, Pouysségur J (1984) Growth factor action and intracellular pH regulation in fibroblasts. J Biol Chem 259: 5809–5815

    Google Scholar 

  14. Paris S, Pouysségur J (1984) Growth factors activate the Na+/H+ antiport in quiescent fibroblasts by increasing its affinity for intracellular H+. J Biol Chem 259: 10989–10994

    Google Scholar 

  15. Rozengurt E, Mendoza SA (1980) Monovalent ion fluxes and the control of cell proliferation in cultured fibroblasts. Ann NY Acad Sci 339: 175–190

    Google Scholar 

  16. L'Allemain G, Franchi A, Cragoe E Jr, Pouysségur J (1984) Blockade of the Na+/H+ antiport abolishes growth factor-induced DNA synthesis in fibroblasts. J Biol Chem 259: 4313–4319

    Google Scholar 

  17. Lopez-Rivas A, Adelberg EA, Rozengurt E (1982) Intracellular K+ and the mitogenic response of 3T3 cells to peptide factors in serum-free medium. Proc Natl Acad Sci USA 79: 6275–6279

    Google Scholar 

  18. Burns CP, Rozengurt E (1984) Extracellular Na+ and initiation of DNA synthesis: role of intracellular pH and K+. J Cell Biol 98: 1082–1089

    Google Scholar 

  19. Rozengurt E, Gelehrter TD, Legg A, Pettican P (1981) Melittin stimulates Na entry, Na−K pump activity and DNA synthesis in quiescent cultures of mouse cells. Cell 23: 781–788

    Google Scholar 

  20. Rozengurt E (1981) Na influx as a mitogenic signal for cultured fibroblasts. In: Mozes CW, Schultz J, Scott WA, Werner R (eds) Cellular responses to molecular modulators. Academic Press, New York, pp 149–168

    Google Scholar 

  21. Lopez-Rivas A, Rozengurt E (1983) Vasopressin rapidly stimulates Ca2+ efflux from an intracellular pool in quiescent fibroblastic cells. Biochem Biophys Res Commun 114: 240–247

    Google Scholar 

  22. Lopez-Rivas A, Mendoza SA, Nanberg E, Sinnett-Smith J, Rozengurt E (1987) The Ca2+-mobilizing actions of platelet-derived growth factor differ from those of bombesin and vasopressin in Swiss 3T3 cells. Proc Natl Acad Sci USA (in press)

  23. Chambard J-C, Pouysségur J (1986) Intracellular pH controls growth factor-induced ribosomal protein S6 phosphorylation and protein synthesis in the G0-G1 transition of fibroblasts. Exp Cell Res 164: 282–294

    Google Scholar 

  24. Reznik VM, Villela J, Mendoza SA (1983) Serum stimulates Na entry and the Na−K pump in quiescent cultures of epithelial cells (MDCK). J Cell Physiol 117: 211–214

    Google Scholar 

  25. Reznik VM, Shapiro RJ, Mendoza SA (1985) Vasopressin stimulates DNA synthesis and ion transport in quiescent epithelial cells. Am J Physiol 249: C267–C270

    Google Scholar 

  26. Smith JB, Rozengurt E (1978) Serum stimulates the Na+/K+ pump in quiescent fibroblasts by increasing Na+ entry. Proc Natl Acad Sci USA 75: 5560–5564

    Google Scholar 

  27. Koch KS, Leffert HL (1979) Increased sodium ion influx is necessary to initiate rat hepatocyte proliferation. Cell 18: 153–163

    Google Scholar 

  28. Mendoza SA, Wigglesworth NM, Rozengurt E (1980) Vasopressin rapidly stimulates Na entry and Na−K pump activity in quiescent cultures of mouse 3T3 cells. J Cell Physiol 105: 153–162

    Google Scholar 

  29. Moolenaar WH, Yarder Y, de Laat SW, Schlessinger J (1982) Epidermal growth factor induces electrically silent Na+ influx in human fibroblasts. J Biol Chem 257: 8502–8506

    Google Scholar 

  30. Owen NE, Villereal ML (1983) Lys-bradykinin stimulates Na+ influx and DNA synthesis in cultured human fibroblasts. Cell 32: 979–985

    Google Scholar 

  31. Villereal ML (1981) Sodium fluxes in human fibroblasts: effect of serum, Ca2+ and amiloride. J Cell Physiol 107: 359–369

    Google Scholar 

  32. Vara F, Rozengurt E (1985) Stimulation of the Na+/H+ antiport by epidermal growth factor and insulin occurs without activation of protein kinase C. Biochem Biophys Res Commun 130: 646–653

    Google Scholar 

  33. Muldoon LL, Dinerstein RJ, Villereal ML (1985) Intracellular pH in human fibroblasts: effect of mitogens, A23187, and phospholipase activation. Am J Physiol 249: C140–C148

    Google Scholar 

  34. Moolenaar WH, Tsien RY, van der Saag PT, de Laat SW (1983) Na+/H+ exchange and cytoplasmic pH in the action of growth factors in human fibroblasts. Nature 304: 645–648

    Google Scholar 

  35. Girard J-P, Payan P, Sardet C (1982) Changes in intracellular cations following fertilization of sea urchin eggs. Exp Cell Res 142: 215–221

    Google Scholar 

  36. Whitaker MJ, Steinhardt RA (1982) Ionic regulation of egg activation. Annu Rev Biophys 15: 593–666

    Google Scholar 

  37. Dube F, Schmidt T, Johnson GH, Epel D (1984) The rise of intracellular pH is transiently required for initiation of early development and increased protein synthesis in sea urchin embryos. J Cell Biol 99: 266a

    Google Scholar 

  38. Mills GB, Cragoe EJ Jr, Gelfand EW, Grinstein S (1985) Interleukin 2 induces a rapid increase in intracellular pH through activation of a Na+/H+ antiport. Cytoplasmic alkalinization is not required for lymphocyte proliferation. J Biol Chem 260: 12500–12507

    Google Scholar 

  39. Moolenaar WH, Boonstra J, van der Saag PT, de Laat SW (1981) Sodium/proton exchange in mouse neuroblastoma cells. J Biol Chem 256: 12883–12887

    Google Scholar 

  40. Benos DJ, Sapirstein VS (1983) Characteristics of an amiloride sensitive sodium entry pathway in cultured rodent glial and neuroblastoma cells. J Cell Physiol 116: 213–220

    Google Scholar 

  41. Boonstra J, Moolenaar WH, Harrison PH, Moed P, van der Saag PT, de Laat SW (1983) Ionic responses and growth stimulation induced by nerve growth factor and epidermal growth factor in rat pheochromocytoma (PC12) cells. J Cell Biol 97: 992–998

    Google Scholar 

  42. Berridge MJ, Irvine RF (1984) Inositol triphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315–321

    Google Scholar 

  43. Kawaguchi H, Yasuda H (1984) Platelet-activating factor stimulates phospholipase in quiescent Swiss mouse 3T3 fibroblasts. FEBS Lett 176: 93–96

    Google Scholar 

  44. Nishizuka Y (1984) The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308: 693–698

    Google Scholar 

  45. Kikkawa U, Takai Y, Tanaka Y, Miyake R, Nishizuka Y (1983) Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters. J Biol Chem 258: 11442–11445

    Google Scholar 

  46. Vara F, Schneider JA, Rozengurt E (1985) Ionic responses rapidly elicited by activation of protein kinase C in quiescent Swiss 3T3 cells. Proc Natl Acad Sci USA 82: 2384–2388

    Google Scholar 

  47. Biden TJ, Prentki M, Irvine RF, Berridge MJ, Wollheim CB (1984) Inositol 1,4,5-trisphosphate mobilizes intracellular Ca2+ from permeabilized insulin-secreting cells. Biochem J 223: 467–473

    Google Scholar 

  48. Berridge MJ, Heslop JP, Irvine RF, Brown KD (1984) Inositol triphosphate formation and calcium mobilization in Swiss 3T3 cells in response to platelet-derived growth factor. Biochem J 222: 195–201

    Google Scholar 

  49. Vicentini LM, Villereal ML (1984) Serum, bradykinin and vasopressin stimulate release of inositol phosphates from human fibroblasts. Biochem Biophys Res Commun 113: 663–670

    Google Scholar 

  50. Rozengurt E, Courtenay-Luck N (1982) Signalling mitogenesis in 3T3 cells: role of monovalent ion fluxes and cyclic nucleotides. Biosci Rep 2: 589–595

    Google Scholar 

  51. Paris S, Rozengurt E (1982) Cyclic AMP stimulation of Na−K pump activity in quiescent Swiss 3T3 cells. J Biol Chem 259: 10989–10994

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of California, San Diego, Mail Code M-009 G, 92093, La Jolla, CA, USA

    Stanley A. Mendoza

Authors
  1. Stanley A. Mendoza
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mendoza, S.A. The role of ion transport in the regulation of cell proliferation. Pediatr Nephrol 2, 118–123 (1988). https://doi.org/10.1007/BF00870391

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00870391

Key words

Search

Navigation