Skip to main content
SpringerLink
Log in

Signal transduction mechanism for the stimulation of the sarcolemmal Na+−Ca2+ exchanger by insulin

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The signal transduction pathway for insulin-mediated activation of sarcolemmal Na+−Ca2+ exchange was examined. Insulin stimulated Na+−Ca2+ exchanger activity in a dose-dependent manner, with the EC50 being about 0.7 U/l. The insulin effect was blocked by the protein kinase inhibitor, staurosporine, indicating possible involvement of a protein kinase in insulin action. Also, the relationship between the insulin effect and activation of a G protein, was examined by testing the effects of 5′ guanylyl imidodiphosphate (Gpp(NH))p) on Na+−Ca2+ exchange in, the presence and absence of insulin. When exchanger activity was assayed at a calcium concentration of 40 μM, insulin alone had no effect whereas ATP and Gpp(NH)p increased exchanger activity. However, insulin responsiveness was restored in vesicles preloaded with either ATP or Gpp(NH)p, suggesting that insulin may act through a combination of G protein coupling and protein phosphorylation to enhance Na+−Ca2+ exchanger activity. We conclude that calcium overload in the diabetic heart may involve a defect in acute activation of the exchanger by insulin.

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. Lawrence Jr: Signal transduction and protein phosphorylation in the regulation of cellular metabolism by insulin. Ann Rev Physiol 54: 177–193, 1992

    Google Scholar 

  2. Larner J: Insulin-signaling mechanisms. Diabetes 37: 262–275, 1988

    Google Scholar 

  3. Saltiel AR, Cuatrecasas P: In search of a second messenger for insulin. Am J Physiol 255: C1-C11, 1988

    Google Scholar 

  4. Farese RV, Cooper DR: Potential role of phospholipid-signaling systems in insulin action and states of clinical insulin resistance. Diabetes/ Metabolism Reviews 5: 455–474, 1989

    Google Scholar 

  5. Makino N, Dhalla KS, Elimban V, Dhalla NS: Sarcolemmal Ca2+ transport in streptozotocin-induced diabetic cardiomyopathy in rats. Am J Physiol 253: E202-E207, 1987

    Google Scholar 

  6. Allo SN, Lincoln TM, Wilson GL, Green FJ, Watanabe AM, Schaffer SW: Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation. Am J Physiol 260: C1165-C1171, 1991

    Google Scholar 

  7. Afzal N, Ganguly PK, Dhalla KS, Pierce GN, Signal PK, Dhalla NS: Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes 37: 936–942, 1988

    Google Scholar 

  8. Schaffer SW: Cardiomyopathy associated with noninsulin-dependent diabetes. Mol Cell Biochem 107: 1–20, 1991

    Google Scholar 

  9. Gupta MP, Innes IR, Dhalla NS: Characterization of insulin receptors in cardiac sarcolemmal and sarcoplasmic reticular membranes. J Cardiovasc Pharmacol 10: 259–267, 1987

    Google Scholar 

  10. Pitts BJR: Stoichiometry of sodium-calcium exchange in cardiac sarcolemmal vesicles. J Biol Chem 254: 6232–6235, 1979

    Google Scholar 

  11. Schaffer SW, Allo S, Punna S, White T: Defective response to cAMP-dependent protein kinase in non-insulin-dependent diabetic heart. Am J Physiol 261: E369-E376, 1991

    Google Scholar 

  12. Reeves JP, Sutko JL: Sodium-calcium ion exchange in cardiac membrane vesicles. Proc Natl Acad Sci USA 76: 590–594, 1979

    Google Scholar 

  13. Farah AE, Alousi AA: The actions of insulin on cardiac contractility. Life Sci 29: 975–1000, 1981

    Google Scholar 

  14. Schaffer SW, Warner BA, Wilson GL: Effects of chronic glipizide treatment on the NIDD heart. Horm Metabol Res 25: 348–353, 1993

    Google Scholar 

  15. Bkaily G, Economos D, Potvin L, Ardilouze J-L, Marriott C, Corcos J, Bonneau D, Fong CN: Blockade of insulin sensitive steady-state R-type Ca2_ channel by PN 200-110 in heart and vascular smooth muscle. Mol Cell Biochem 117: 93–106, 1992

    Google Scholar 

  16. Gupta MP, Lee S-L, Dhalla NS: Activation of heart sarcoplasmic reticulum Ca2+-stimulated adenosine triphosphatase by insulin. J Pharmacol Exp Therap 249: 623–630, 1989

    Google Scholar 

  17. Dipolo R, Beauge L: Regulation of Na−Ca exchange. Ann N Y Acad Sci 639: 100–111, 1991

    Google Scholar 

  18. Reeves JP, Philipson KD: Sodium-calcium exchange activity in, plasma membrane vesicles. In: T.J.A. Allen, D. Noble and H. Reuter (eds) Sodium-calcium Exchange. Oxford University Press, Oxford, 1989, pp 27–53

    Google Scholar 

  19. Philipson KD, Nicoll DA: Molecular and kinetic aspects of sodiumcalcium exchange. Int Rev Cytology 137C: 199–227, 1993

    Google Scholar 

  20. Haworth RA, Goknur AB: ATP dependence of calcium uptake by the Na−Ca exchanger of adult heart cells. Circ Res 71: 210–217, 1992

    Google Scholar 

  21. Caroni P, Carafoli E: The regulation of the Na+−Ca2+ exchanger of heart sarcolemma. Eur J Biochem 132: 451–460, 1983

    Google Scholar 

  22. Vigne P, Breittmayer J-P, Duval D, Frelin C, Lazdunski M: The Na+/Ca2+ antiporter in aortic smooth muscle cells. J Biol Chem 263: 8078–8083, 1988

    Google Scholar 

  23. Collins A, Somlyo AV, Hilgemann DW: The giant cardiac membrane patch method: stimulation of outward Na+−Ca+ exchange current by MgATP. J Physiol 454: 27–57, 1992

    Google Scholar 

  24. Hilgemann DW, Collins A: Mechanism of cardiac Na+−Ca2+ exchange current stimulation by MgATP: possible involvement of aminophospholipid translocase. J Physiol 454: 59–82, 1992

    Google Scholar 

  25. Cirillo M, Canessa ML: Activation of Ca2+−Na+ exchange by platelet-derived growth factor in vascular smooth muscle cells. Ann NY Acad Sci 639: 169–171, 1991

    Google Scholar 

  26. Lindmar R, Löffelholz K: Phospholipase D in heart: basal activity and stimulation by phorbol esters and aluminium fluoride. Naunyn-Schmiedeberg's Arch Pharmacol 346: 607–613, 1992

    Google Scholar 

  27. Philipson KD, Nishimoto AY: Stimulation of Na+−Ca2+ exchange in cardiac sarcolemmal vesicles by phospholipase D. J Biol Chem 259: 16–19, 1984

    Google Scholar 

  28. Yano Y, Sumida Y, Benzing CF, Robinson FW, Kono T: Primary sites of actions of staurosporine and H-7 in the cascade of insulin action to glucose transport in rat adipocytes. Biochim Biophys Acta 1176: 327–332, 1993

    Google Scholar 

  29. Brechler V, Pavoine C, Lotersztajn S, Garbarz E, Pecker F: Activation of Na+/Ca2+ exchange by adenosine in ewe heart sarcolemma is mediated by a pertussis toxin-sensitive G protein. J Biol Chem 265: 16851–16855, 1990

    Google Scholar 

  30. Russ M, Reinauer H, Eckel J: Regulation of cardiac insulin receptor function by guanosine nucleotides. FEBS Lett 314: 72–76, 1992

    Google Scholar 

  31. Burdett E, Mills GB, Klip A: Effect of GTPγS on insulin binding and tyrosine phosphorylation in liver membranes and L6 muscle cells. Am J Physiol 258: C99-C108, 1990

    Google Scholar 

  32. Hadcock JR, Port JD, Gelman MS, Malbon CC: Cross-talk between tyrosine kinase and G-protein-linked receptors. J Biol Chem 267: 26017–26022, 1992

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Medicine, Department of Pharmacology, University of South Alabama, 36688, Mobile, AL, USA

    Cherry Ballard, Mahmood Mozaffari & Stephen Schaffer

Authors
  1. Cherry Ballard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmood Mozaffari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen Schaffer
    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

Ballard, C., Mozaffari, M. & Schaffer, S. Signal transduction mechanism for the stimulation of the sarcolemmal Na+−Ca2+ exchanger by insulin. Mol Cell Biochem 135, 113–119 (1994). https://doi.org/10.1007/BF00925967

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00925967

Key words

Search

Navigation