Skip to main content
SpringerLink
Log in

Involvement of NMDA Receptor in the Modulation of Excitatory and Inhibitory Amino Acid Neurotransmitters Release in Cortical Neurons

  • ORIGINAL PAPER
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The purpose of this paper was to examine the function of N-methyl-D-aspartate (NMDA) glutamate receptor in cortical neurons on amino acid neurotransmitters release as well as the fraction of neurons implicated in the response of this receptor. Local stimulation of these cells at different concentrations of NMDA, agonist of this ionotropic glutamate receptor, produced a dose dependent release of aspartate, glutamate, glycine and GABA. These effects were blocked by DAP5, an antagonist of the NMDA receptor. The amino acid Ca2+ dependent release mediated by the NMDA receptor, is induced by the opening of voltage-dependent Ca2+ channels that this receptor promotes. Ca++ movements were explored in single cells loaded with fura-2. When single cells were stimulated with 100 μM NMDA, the calcium recording performed showed that 82% of the cells responded to this agonist increasing the intracellular calcium concentration, although the amplitude of these increments was variable. The results suggest that NMDA-elicited neurotransmitter release from cortical neurons involves Ca2+-dependent and Ca2+-independent components, as well as neuron depolarisation, and different VDCC subtypes of N, P/Q or L depending of the amino acid neurotransmitter release elicited by this receptor.

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

Similar content being viewed by others

References

  1. De Belleroche J, Recordati A, Rose FC (1984) Elevated levels of amino acids in the CSF of moto neuron disease patients. Neurochem Pathol 2:1–6

    Article  PubMed  Google Scholar 

  2. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    Article  CAS  PubMed  Google Scholar 

  3. Lipton SA, Kater SB (1989) Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci 12:265–270

    Article  CAS  PubMed  Google Scholar 

  4. Meldrum B, Garthwaite J (1990) Excitatory amino acid neurotoxicity and neurodegenerative disease. Trend Pharmacol Sci 11:379–387

    Article  CAS  Google Scholar 

  5. Nei K, Matsuyama S, Shuntoh H et al (1996) NMDA receptor activation induces glutamate release through nitric oxide synthesis in guinea pig dentate gyrus. Brain Res 728:105–110

    Article  CAS  PubMed  Google Scholar 

  6. Fontana G, De Bernardi R, Ferro F et al (1996) Characterization of the glutamate receptors mediating release of somatostatin from cultured hippocampal neurons. J Neurochem 66:161–168

    Article  CAS  PubMed  Google Scholar 

  7. Cheramy A, Godeheu G, L`Hirondel M et al (1996) Cooperative contributions of cholinergic and NMDA receptors in the presynaptic control of dopamine release from synaptosomes of the rat striatum. J Pharmacol Exp Ther 276:616–625

    CAS  PubMed  Google Scholar 

  8. Garcia Y, Ibarra C, Jaffe EH (1995) NMDA and non-NMDA receptor-mediated release of [3H] GABA from granule cell dendrites of rat olfactory bulb. J Neurochem 64:662–669

    Article  CAS  PubMed  Google Scholar 

  9. Janaky R, Varga V, Oja SS et al (1994) Release of [3H] GABA evoked by glutamate agonists from hippocampal slices: effect of dithiothreitol and glutathione. Neurochem Int 24:575–582

    Article  CAS  PubMed  Google Scholar 

  10. Young AM, Bradford HF (1993) N-methyl-D-aspartate releases gamma-aminobutyric acid from rat striatum in vivo: a microdialysis study using a novel preloading method. J Neurochem 60:487–492

    Article  CAS  PubMed  Google Scholar 

  11. Puttfarcken PS, Handen JS, Montgomery DT et al (1993) N-Acethyl-aspartylglutamate modulation of N-methyl-D-aspartate-stimulated [3H]norepinephrine release from rat hippocampal slices. J Pharmacol Exp Ther 266:796–803

    CAS  PubMed  Google Scholar 

  12. Jedema HP, Moghddam B (1996) Characterization of excitatory amino acid modulation of dopamine release in the prefrontal cortex of conscious rats. J Neurochem 66:1448–1453

    Article  CAS  PubMed  Google Scholar 

  13. Toth E, Sershen H, Hashim A et al (1992) Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid. Neurochem Res 17:265–271

    Article  CAS  PubMed  Google Scholar 

  14. Kendrick KM, Guevara-Guzman R, De la Riva C et al (1996) NMDA and kainate-evoked release of nitric oxide and classical transmitters in the rat striatum: in vivo evidence that nitric oxide may play a neuroprotective role. Eur J Neurosci 8:2619–2634

    Article  CAS  PubMed  Google Scholar 

  15. Smolders I, Sarre S, Vanhaesendonck C et al (1996) Extracellular striatal dopamine and glutamate after decortication and kainite receptor stimulation, as measured by microdialysis. J Neurochem 66:2373–2380

    Article  CAS  PubMed  Google Scholar 

  16. Tanaka J, Miyakubo H, Kawakami A et al (2006) Involvement of NMDA receptor mechanisms in the modulation of serotonin release in the lateral parabranchial nucleus in the rat. Brain Res Bull 71:311–315

    Article  CAS  PubMed  Google Scholar 

  17. Paes PCA, De Magalhaes L, Camillo MAP et al (2004) Ionotropic glutamate receptors regulating labeled acetylcholine release from rat striatal tissue in vitro: possible involvement of receptor modulation in magnesium sensitivity. Neurosc Res 49:289–295

    Article  CAS  Google Scholar 

  18. Kater SB, Mattson MP, Cohan C et al (1988) Calcium regulation of the neural growth cone. Trends Neurosci 11:315–321

    Article  CAS  PubMed  Google Scholar 

  19. McDonald JW, Johnston MV (1990) Physiological and pathophysiological roles of excitatory amino acids during the central nervous system development. Brain Res 15:41–70

    Article  Google Scholar 

  20. Stout AK, Woodward JJ (1994) Differential effects of nitric oxide gas and nitric oxide donors on depolarization-induced release of [3H]norepinephrine from rat hippocampal slices. Neuropharmacology 33:1367–1374

    Article  CAS  PubMed  Google Scholar 

  21. Jones NM, Loiacono RE, Beart PM (1995) Roles for nitric oxide as intra- and interneuronal messenger at NMDA release-regulating receptors: evidence from studies of the NMDA-evoked release of [3H]noradrenaline and D-[3H]aspartate from rat hippocampal slices. J Neurochem 64:2057–2063

    Article  CAS  PubMed  Google Scholar 

  22. Moller M, Jones NM, Beart PM (1995) Complex involvement of nitric oxide and cGMP at N-methyl-D-aspartic acid receptors regulating gamma-[3H]aminobutyric acid release from striatal slices. Neurosci Lett 190:195–198

    Article  CAS  PubMed  Google Scholar 

  23. Dumuis A, Sebben M, Haynes L et al (1988) NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 336:68–70

    Article  CAS  PubMed  Google Scholar 

  24. Barbour B, Szatkowski M, Ingledew N et al (1989) Arachidonic acid induces a prolonged inhibition of glutamate uptake into glial cells. Nature 342:918–920

    Article  CAS  PubMed  Google Scholar 

  25. Bouchard R, Pattarini R, Geiger JD (2003) Presence and functional significance of presynaptic ryanodine receptors. Prog Neurobiol 69:391–418

    Article  CAS  PubMed  Google Scholar 

  26. Collin T, Marty A, Llano I (2006) Presynpatic Ca2+ stores and synaptic transmission. Curr Opin Neurobiol 15:275–281

    Article  Google Scholar 

  27. Bardo S, Cavazzini MG, Emptage N (2006) The role of endoplasmic reticulum Ca2+-store in the plasticity of central neurons. Trends Pharmacol Sci 27:78–84

    Article  CAS  PubMed  Google Scholar 

  28. Rusakov DA (2006) Ca2+-dependent mechanisms of presynaptic control at central synapses. Neuroscientist 12:317–326

    Article  CAS  PubMed  Google Scholar 

  29. Christie JM, Jahr CE (2008) Dendritic NMDA receptors activate axonal calcium channels. Neuron 60:298–307

    Article  CAS  PubMed  Google Scholar 

  30. Segal M (1983) Rat hippocampal neurons in culture: responses to electrical and chemical stimuli. J Neurophysiol 50:1249–1264

    CAS  PubMed  Google Scholar 

  31. Marquez FJ, Quesada AR, Sanchez-Jimenez F et al (1986) Determination of 27 dansyl amino acid derivatives in biological fluids by reversed-phase high-performance liquid chromatography. J Chromatogr 380:275–283

    Article  CAS  PubMed  Google Scholar 

  32. Bradford M (1976) A rapid sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–253

    Article  CAS  PubMed  Google Scholar 

  33. Tsien RY, Hladky SB (1978) A quantitative resolution of spectra of a membrane potential indicator, diS-C3-(5), bound to cell components and to red blood cells. J Membr Biol 38:73–97

    Article  CAS  PubMed  Google Scholar 

  34. Waggoner AS (1979) Dye indicators of membrane potential. Annu Rev Biophys Bioeng 8:47–68

    Article  CAS  PubMed  Google Scholar 

  35. Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450

    CAS  PubMed  Google Scholar 

  36. Szatkowski M, Barbour B, Attwell D (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic uptake. Nature 348:443–446

    Article  CAS  PubMed  Google Scholar 

  37. Sundström E, Mo L-L, Seiger A (1995) In vivo studies on NMDA-evoked release of amino acids in the rat spinal cord. Neurochem Int 2:185–193

    Article  Google Scholar 

  38. Brosius DC, Hackett JT, Tuttle JB (1992) Ca2+-independent and Ca2+-dependent stimulation of quantal neurosecretion in avian ciliary ganglion neurons. J Neurophysiol 68:1229–1234

    CAS  PubMed  Google Scholar 

  39. Yoshimura H, Sugai T, Onoda N et al (2001) Synchronized population oscillation of excitatory synaptic potentials dependent of calcium-induced calcium release in rat neocortex layer II/III neurons. Brain Res 915:94–100

    Article  CAS  PubMed  Google Scholar 

  40. Gao WJ, Goldman-Rakic PS (2006) NMDA receptor-mediated epiteliform persistent activity requires calcium release from intracellular stores in prefrontal neurons. Exp Neurol 197:495–504

    Article  CAS  PubMed  Google Scholar 

  41. Fossier P, Baux G, Trudeau LE et al (1992) Involvement of Ca2+-uptake by a reticulum-like store in the control of transmitter release. Neuroscience 50:427–434

    Article  CAS  PubMed  Google Scholar 

  42. Courtney MJ, Nicholls DG (1992) Interactions between phospholipase C-coupled and N-methyl-D-aspartate receptors in cultured cerebellar granule cells: protein kinase C mediated inhibition of N-methyl-D-aspartate responses. J Neurochem 59:983–992

    Article  CAS  PubMed  Google Scholar 

  43. Simpson PB, Challiss RA, Nahorski SR (1995) Neuronal Ca2+ stores: activation and function. Trends Neurosci 18:299–306

    Article  CAS  PubMed  Google Scholar 

  44. McMahon HT, Nicholls DG (1990) Glutamine and aspartate loading of synaptosomes: a reevaluation of effects on calcium-dependent excitatory amino acid release. J Neurochem 54:373–380

    Article  CAS  PubMed  Google Scholar 

  45. Zhou M, Peterson CL, Lu YB et al (1995) Release of glutamate and aspartate from CA1 synaptosomes: selective modulation of aspartate release by ionotropic glutamate receptor ligands. J Neurochem 64:1556–1566

    Article  CAS  PubMed  Google Scholar 

  46. Nicholls D, Attwell D (1990) The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:462–468

    Article  PubMed  Google Scholar 

  47. Ragozzino D, Eusebi F (1993) Inhibition of GABA and glycine responses by glutamate in rat hippocampal neurons. Brain Res 628:115–120

    Article  CAS  PubMed  Google Scholar 

  48. Shahi K, Baudry M (1993) Glycine-induced changes in synaptic efficacy in hippocampal slices involve changes in AMPA receptors. Brain Res 627:261–266

    Article  CAS  PubMed  Google Scholar 

  49. Danysz W, Parsons CG (1998) Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 50:597–664

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the grants SAF2006-05563 from Ministry of Education (MEC, Spain) and CCG07-UCM/SAL-3024 (Complutense University/Madrid Community). The authors thank to Mikel Erdocia Arce for his help in improving the manuscript.

Author information

Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, UCM, Ciudad Universitaria, 28040, Madrid, Spain

    E. López, J. Hernandez, C. Arce, S. Cañadas, M. J. Oset-Gasque & M. P. González

  2. Centro de Investigaciones Biológicas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu, 9, 28040, Madrid, Spain

    E. López & M. P. González

Authors
  1. E. López
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Arce
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Cañadas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. J. Oset-Gasque
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. P. González
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. P. González.

Rights and permissions

Reprints and permissions

About this article

Cite this article

López, E., Hernandez, J., Arce, C. et al. Involvement of NMDA Receptor in the Modulation of Excitatory and Inhibitory Amino Acid Neurotransmitters Release in Cortical Neurons. Neurochem Res 35, 1478–1486 (2010). https://doi.org/10.1007/s11064-010-0209-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-010-0209-0

Keywords

Search

Navigation