Sodium-Calcium Exchanger Modulates the L-Glutamate Cai2+ Signalling in Type-1 Cerebellar Astrocytes

  • Héctor Rojas
  • Claudia Colina
  • Magaly Ramos
  • Gustavo Benaim
  • Erica Jaffe
  • Carlo Caputo
  • Reinaldo Di PoloEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)


We have previously demonstrated that rat type-1 cerebellar astrocytes express a very active Na+/Ca2+ exchanger which accounts for most of the total plasma membrane Ca2+ fluxes and for the clearance of Ca i 2+ induced by physiological agonist. In this chapter, we have explored the mechanism by which the reverse Na+/Ca2+ exchange is involved in agonist-induced Ca2+ signalling in rat cerebellar astrocytes. Laser-scanning confocal microscopy experiments using immunofluorescence labelling of Na+/Ca2+ exchanger and RyRs demonstrated that they are highly co-localized. The most important finding presented in this chapter is that L-glutamate activates the reverse mode of the Na+/Ca2+ exchange by inducing a Na+ entry through the electrogenic Na+-glutamate co-transporter and not through the ionophoric L-glutamate receptors as confirmed by pharmacological experiments with specific blockers of ionophoric L-glutamate receptors, electrogenic glutamate transporters and the Na/Ca exchange.


Na+/Ca2+ exchange CICR Glutamate Glutamate transporter 



This work was supported by FONACIT-Venezuela (G-0010000637).


  1. P.K. Aley, H.J. Murray, J.P. Boyle, H.A. Pearson, C. Peers, Hypoxia stimulates Ca2+ release from intracellular stores in astrocytes via cyclic ADP ribose-mediated activation of ryanodine receptors. Cell Calcium 39, 95–100 (2006)PubMedCrossRefGoogle Scholar
  2. A. Araque, N. Li, R.T. Doyle, P.G. Haydon, SNARE ­protein-dependent glutamate release from astrocytes. J. Neurosci. 20, 666–673 (2000)PubMedGoogle Scholar
  3. A. Beck, R.Z. Nieden, H.P. Scheideer, J.W. Ditmer, Calcium release from intracellular stores in rodent astrocytes and neurons in situ. Cell Calcium 35, 47–58 (2004)PubMedCrossRefGoogle Scholar
  4. B. Benz, G. Grima, K.Q. Do, Glutamate-induced homocysteic acid release from astrocytes: possible implication in glia-neuron signalling. Neuroscience 124, 377–386 (2004)PubMedCrossRefGoogle Scholar
  5. M.P. Blaustein, J. Lederer, Sodium/calcium exchange: its physiological implication. Physiol. Rev. 79, 763–854 (1999)PubMedGoogle Scholar
  6. F. Calegari, S. Coco, E. Taverna, M. Bassetti, C. Verderio, N. Corradi, M. Matteoti, P. Rosa, A regulated secretory pathway in cultured hippocampal astrocytes. J. Biol. Chem. 274, 22539–22547 (1999)PubMedCrossRefGoogle Scholar
  7. T. Fellin, G. Carmignoto, Neurone-to-astrocyte signalling in the brain represents a distinct multifunctional unit. J. Physiol. 559, 3–15 (2004)PubMedCrossRefGoogle Scholar
  8. W.F. Goldman, P.J. Yarowsky, M. Juhaszova, B.K. Krueger, M.P. Blaustein, Sodium/calcium exchange in rat cortical astrocytes. J. Neurosci. 14, 5834–5843 (1994)PubMedGoogle Scholar
  9. V.A. Golovina, M.P. Blaustein, Unloading and refilling of two classes of spatially resolved endoplasmic reticulum Ca2+ stores in astrocytes. Glia 31, 15–28 (2000)PubMedCrossRefGoogle Scholar
  10. C. Greever, T. Rauen, Electrogenic glutamate transporters in the CNS: molecular mechanism, pre-steady state kinetics, and their impact on synaptic signaling. J. Memb. Biol. 203, 1–20 (2005)PubMedCrossRefGoogle Scholar
  11. X. Hua, E.B. Melarkey, V. Sunjara, S.E. Rosenwald, W.H. Li, V. Parpura, Ca2+-dependent glutamate release involves two classes of endoplasmic reticulum Ca2+ stores in astrocytes. J. Neurosci. Res. 76, 86–97 (2004)PubMedCrossRefGoogle Scholar
  12. J. Hurtado, S. Borges, M. Wilson, Na+-Ca2+ exchanger controls the gain of the Ca2+ amplifier in the dendrites of amacrine cells. J. Neurophysiol. 88, 2765–2777 (2002)PubMedCrossRefGoogle Scholar
  13. S.D. Jeftinija, K.V. Jeftinija, G. Stefanovic, Cultured astrocytes express proteins involved in vesicular glutamate release. Brain Res. 750, 41–47 (1997)PubMedCrossRefGoogle Scholar
  14. M. Juhaszova, H. Shimizu, M.L. Borin, R.K. Yip, E.M. Santiago, G.E. Lindenmayer, M.P. Blaustein, Localization of the Na+-Ca2+ exchanger in vascular smooth muscle, and in neurons and astrocytes. Ann. N. Y. Acad. Sci. 779, 318–335 (1996)PubMedCrossRefGoogle Scholar
  15. M. Kano, O. Garaschuk, A. Verkhratsky, A. Konnerth, Ryanodine receptor-mediated intracellular calcium release in rat cerebellar Purkinje neurones. J. Physiol. 487, 1–16 (1995)PubMedGoogle Scholar
  16. M.H. Kin-Lee, B.T. Stoke, A.J. Yates, Reperfusion paradox: a novel mode of glial cell injury. Glia 5, 56–64 (1992)CrossRefGoogle Scholar
  17. D. Langley, B. Pearce, Ryanodine-induce intracellular calcium mobilization in culture astrocytes. Glia 12, 128–134 (1994)PubMedCrossRefGoogle Scholar
  18. I. Llano, J. Gonzalez, C. Caputo, F.A. Lai, L.M. Blaynet, Y.P. Tan, A. Marty, Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients. Nat. Neurosci. 3, 1256–1265 (2000)PubMedCrossRefGoogle Scholar
  19. K. Lo, H.N. Luk, T.Y. Chin, S.H. Chueh, Store depletion-induced calcium influx in rat cerebellar astrocytes. Br. J. Pharmacol. 135, 1383–1392 (2002)PubMedCrossRefGoogle Scholar
  20. T. Iwamoto, T. Watano, M. shigegawa, A novel isothiourea frrivative selectivele inhibits de reverse mode of Na/Ca exchange in cells expresing NCX1. J Biol Biochem. 271, 22391–23397 (1998)PubMedGoogle Scholar
  21. T. Matsuda, K. Takuma, E. Nishiguchi, H. Hashimoto, J. Azuma, A. Baba, Involvement of Na+-Ca2+ exchanger in reperfusion-induced delayed cell death of cultured rat astrocytes. Eur. J. Neurosci. 8, 951–958 (1996)PubMedCrossRefGoogle Scholar
  22. M. Matyash, V. Matyash, C. Nolte, V. Sorrentino, H. Kettenmann, Requirement of functional ryanodine receptor type 3 for astrocyte migration. FASEB. J. 16, 84–86 (2002)PubMedGoogle Scholar
  23. M.A. Micci, B.N. Cristensen, Na+/Ca2+ exchange in catfish retina horizontal cells: regulation of intracellular Ca2+ store function. Am. J. Physiol. 274, C1625–C1633 (1998)PubMedGoogle Scholar
  24. M.A. Nazer, C. van Breemen, Functional linkage of Na+-Ca2+ exchange and sarcoplasmic reticulum Ca2+ release mediates Ca2+ cycling in vascular smooth muscle. Cell Calcium 24, 275–283 (1998)PubMedCrossRefGoogle Scholar
  25. V. Parpura, T.A. Basarsky, F. Liu, S. Jeftinija, P.G. Haydon, Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994)PubMedCrossRefGoogle Scholar
  26. L. Pasti, T. Pozzan, G. Carmignoto, Long-lasting changes of calcium oscillations in astrocytes. A new form of glutamate-mediated plasticity. J. Biol. Chem. 270, 15203–15210 (1995)PubMedCrossRefGoogle Scholar
  27. H. Rojas, M. Ramos, R. DiPolo, A genistein-sensitive Na+/Ca2+ exchange is responsible for the resting [Ca2+]i and most of the Ca2+ plasma membrane fluxes in stimulated rat cerebellar type 1 astrocytes. Jpn. J. Physiol. 54, 249–262 (2004)PubMedCrossRefGoogle Scholar
  28. H. Rojas, C. Colina, M. Ramos, G. Benaim, H. Jaffe, C. Caputo, R. Dipolo, Na+ entry via glutamate transporter activates the reverse Na+/Ca2+ exchange and triggers Cai2+-induced Ca2+ release in rat cerebellar Type-1 astrocytes. J. Neurochem. 100, 1188–1202 (2007)PubMedCrossRefGoogle Scholar
  29. P.B. Simpson, S. Mehotra, D. Langley, C.A. Sheppard, J.T. Russell, Specialized distribution of mitochondria and endoplasmic reticulum proteins define Ca2+ wave amplification sites in cultured astrocytes. J. Neurosci. Res. 52, 672–683 (1998a)PubMedCrossRefGoogle Scholar
  30. P.B. Simpson, L.A. Holtzclaw, D.B. Langley, J.T. Russel, Characterization of ryanodine receptors in oligodendrocytes, type 2 astrocytes, and O-2A progenitors. J. Neurosci. Res. 52, 468–482 (1998b)PubMedCrossRefGoogle Scholar
  31. K. Takuma, T. Matsuda, H. Hashimoto, S. Asano, A. BaBa, Culture rat astrocytes posses Na+-Ca2+ exchanger. Glia 12, 336–342 (1994)PubMedCrossRefGoogle Scholar
  32. K. Takuma, T. Matsuda, U. Hashimoto, J. Kitanaka, S. Asano, A. Baba, Role of Na+-Ca2+ exchanger in agonist-induce Ca2+ signalling in cultured rat astrocytes. J. Neurochem. 67, 1840–1845 (1996)PubMedCrossRefGoogle Scholar
  33. H. Uneyama, M. Munakata, N. Akaike, Caffeine response in pyramidal neurones freshly dissociated from rat hippocampus. Brain Res. 604, 24–31 (1993)PubMedCrossRefGoogle Scholar
  34. Y. Usachev, A. Shmigol, P. Pronchuk, A. Kostyuk, A. Verkhratsky, Caffeine-induce calcium release from internal stores in cultured rat sensory neurones. Neuroscience 57, 845–859 (1993)PubMedCrossRefGoogle Scholar
  35. A. Verkhratsky, H. Kettenmann, Calcium signalling in glial cells. TINS 19, 346–352 (1994)Google Scholar
  36. A. Verkhratsky, A. Shmilgol, Calcium-induce calcium release in neurons. Cell Calcium 19, 1–14 (1996)PubMedCrossRefGoogle Scholar
  37. C. Vermeiren, M. Najimi, M. Vanhoutte, S. Tilleux, L. de Hemptinne, J.M. Maloteaux, E. hermans, Acute up-regulation of glutamate uptake mediated by mGluR5a in reactive astrocytes. J. Neurochem. 94, 405–416 (2005)Google Scholar
  38. D.J.A. Wyllie, A. Mathie, C.D. Symonds, S.G. Cull-Candy, Activation of glutamate receptors and mGluR5a Glutamate uptake in identified macroglial cells in rat cerebellar culture. J. Physiol. 432, 235–258 (1991)Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Héctor Rojas
    • 1
  • Claudia Colina
    • 1
  • Magaly Ramos
    • 1
  • Gustavo Benaim
    • 2
  • Erica Jaffe
    • 1
  • Carlo Caputo
    • 1
  • Reinaldo Di Polo
    • 1
    Email author
  1. 1.Laboratorio de Fisiología CelularCentro de Biofísica, Instituto Venezolano de Investigaciones Científicas (IVIC)CaracasVenezuela
  2. 2.Laboratorio de Señalización CelularInstituto de Estudios Avanzados (IDEA)CaracasVenezuela

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