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Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems

Nature Neuroscience volume 2, pages 234–240 (1999)Cite this article

Abstract

The metabotropic glutamate receptor, mGluR5, has a critical role in induction of NMDA-receptor-dependent forms of synaptic plasticity and excitotoxicity. This is likely mediated by a reciprocal positive-feedback interaction between these two glutamate receptor subtypes in which activation of mGluR5 potentiates NMDA receptor currents and NMDA receptor activation potentiates mGluR5-mediated responses. We have investigated the mechanism by which NMDA receptor activation modulates mGluR5 function and find evidence that this response is mediated by activation of a protein phosphatase and a resultant dephosphorylation of protein kinase C phosphorylation sites on mGluR5. This form of neuromodulation may be important in a number of normal and pathological processes that involve activation of the NMDA receptor.

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Figure 1: NMDA receptor activation reduces mGluR5 desensitization in Xenopus oocytes.
Figure 2: NMDA does not potentiate non-desensitized mGluR5-mediated responses.
Figure 3: Phosphatase inhibitors block the NMDA-induced reversal of desensitization.
Figure 4: NMDA reverses PKC-mediated desensitization in CA3 neurons via activation of a protein phosphatase.
Figure 5: NMDA reverses DHPG-induced phosphorylation of mGluR5a in cultured cortical neurons.

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References

  1. Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

    Article  CAS  Google Scholar 

  2. McBain, C. J. & Mayer, M. L. N-methyl-D-aspartic acid receptor structure and function. Physiol. Rev. 74, 723–760 (1994).

    Article  CAS  Google Scholar 

  3. Conn, P. J. & Pin, J. P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205–237 (1997).

    Article  CAS  Google Scholar 

  4. Collingridge, G. L. & Bliss, T. V. P. Memories of NMDA receptors and LTP. Trends Neurosci. 18, 54–56 (1995).

    Article  CAS  Google Scholar 

  5. Brodin, L. & Shupliakov, O. Functional diversity of central glutamate synapses—pre- and post-synaptic mechanisms. Acta Physiol. Scand. 150, 1–10 (1994).

    Article  CAS  Google Scholar 

  6. Rothman, S. M. & Olney, J. W. Excitotoxicity and the NMDA receptor—still lethal after eight years. Trends Neurosci. 18, 57–58 (1995).

    CAS  PubMed  Google Scholar 

  7. Ciabarra, A. M. et al. Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J. Neurosci. 15, 6498–6508 (1995).

    Article  CAS  Google Scholar 

  8. Sucher, N. J. et al. Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J. Neurosci. 15, 6509–6520 (1995).

    Article  CAS  Google Scholar 

  9. Das, S. et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393, 377–381 (1998).

    Article  CAS  Google Scholar 

  10. Harvey, J. & Collingridge, G. L. Signal transduction pathways involved in the acute potentiation of NMDA responses by 1S,3R-ACPD in rat hippocampal slices. Br. J. Pharmacol. 109, 1085–1090 (1993).

    Article  CAS  Google Scholar 

  11. Aniksztejn, L., Otani, S. & Ben-Ari, Y. Quisqualate metabotropic receptors modulate NMDA currents and facilitate induction of long-term potentiation through protein kinase C. Eur. J. Neurosci. 4, 500–505 (1992).

    Article  Google Scholar 

  12. Fitzjohn, S. M. et al. Activation of group I mGluRs potentiates NMDA responses in rat hippocampal slices. Neurosci. Lett. 203, 211–213 (1996).

    Article  CAS  Google Scholar 

  13. Romano, C. et al. Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J. Comp. Neurol. 355, 455–469 (1995).

    Article  CAS  Google Scholar 

  14. Lüthi, A., Gähwiler, B. H. & Gerber, U. Potentiation of a metabotropic glutamatergic response following NMDA receptor activation in rat hippocampus. Pflugers Arch. 427, 197–202 (1994).

    Article  Google Scholar 

  15. Challiss, R. A. J., Mistry, R., Gray, D. W. & Nahorski, S. R. Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic glutamate receptor agonist 1S, 3R-ACPD in neonatal rat cerebral cortex. Br. J. Pharmacol. 112, 231–239 (1994).

    Article  CAS  Google Scholar 

  16. Lu, Y. M. et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17, 5196–5205 (1997).

    Article  CAS  Google Scholar 

  17. Collins, D. R., Scollon, J. M., Russell, D. C. & Davies, S. N. Indirect potentiation of synaptic transmission by metabotropic glutamate receptors in the rat hippocampal slice. Brain Res. 684, 165–171 (1995).

    Article  CAS  Google Scholar 

  18. Angenstein, F. & Staak, S. Receptor-mediated activation of protein kinase C in hippocampal long-term potentiation: facts, problems and implications. Prog. Neuropsychopharmacol. Biol. Psychiatry 21, 427–454 (1997).

    Article  CAS  Google Scholar 

  19. Bortolotto, Z. A. et al. Studies on the role of metabotropic glutamate receptors in long-term potentiation: some methodological considerations. J. Neurosci. Methods 59, 19–24 (1995).

    Article  CAS  Google Scholar 

  20. Sacaan, A. I. & Schoepp, D. D. Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage. Neurosci. Lett. 139, 77–82 (1992).

    Article  CAS  Google Scholar 

  21. Bruno, V. et al. Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells. Neuropharmacology 34, 1089–1098 (1995).

    Article  CAS  Google Scholar 

  22. Gereau, R. W. & Heinemann, S. F. Role of protein kinase C phosphorylation in rapid desensitization of metabotropic glutamate receptor 5. Neuron 20, 143–151 (1998).

    Article  CAS  Google Scholar 

  23. Wang, J. H. & Stelzer, A. Inhibition of phosphatase 2B prevents expression of hippocampal long-term potentiation. Neuroreport 5, 2377–2380 (1994).

    Article  CAS  Google Scholar 

  24. Halpain, S., Girault, J. A. & Greengard, P. Activation of NMDA receptors induces dephosphorylation of DAARP-32 in rat striatal slices. Nature 343, 369–372 (1990).

    Article  CAS  Google Scholar 

  25. Halpain, S. & Greengard, P. Activation of NMDA receptors induces rapid dephosphorylation of the cytoskeletal protein MAP2. Neuron 5, 237–246 (1990).

    Article  CAS  Google Scholar 

  26. Sugiyama, H., Ito, I. & Hirono, C. A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325, 531–533 (1987).

    Article  CAS  Google Scholar 

  27. Sugiyama, H., Ito, I. & Watanabe, M. Glutamate receptor subtypes may be classified into two major categories: a study of Xenopus oocytes injected with rat brain mRNA. Neuron 3, 129–132 (1989).

    Article  CAS  Google Scholar 

  28. Barish, M. E. A transient calcium-dependent chloride current in the immature Xenopus oocyte. J. Physiol. (Lond.) 342, 309–325 (1983).

    Article  CAS  Google Scholar 

  29. Palmer, E., Monaghan, D. T. & Cotman, C. W. Glutamate receptors and phosphoinositide metabolism: stimulation via quisqualate receptors is inhibited by N-methyl-D-aspartate receptor activation. Mol. Brain Res. 4, 161–165 (1988).

    Article  CAS  Google Scholar 

  30. Morari, M. et al. Excitatory amino acids (EAAs) stimulate phosphatidylinositol turnover in adult rat striatal slices: Interaction between NMDA and EAA metabotropic receptors. Neurochem. Int. 24, 191–200 (1994).

    Article  CAS  Google Scholar 

  31. Morari, M. et al. Inhibitory effect of NMDA receptor activation on quisqualate-stimulated phosphatidylinositol turnover in the human cerebral cortex. Brain Res. 553, 14–17 (1991).

    Article  CAS  Google Scholar 

  32. Yakel, J. L. Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription. Trends Pharmacol. Sci. 18, 124–133 (1997).

    Article  CAS  Google Scholar 

  33. Enan, E. & Matsumura, F. Specific inhibition of calcineurin by type II synthetic pyrethroid insecticides. Biochem. Pharmacol. 43, 1777–1784 (1992).

    Article  CAS  Google Scholar 

  34. Doherty, A. J., Palmer, M. J., Henley, J. M., Collingridge, G. L. & Jane, D. E. (RS)-2-chloro-5- hydroxyphenylglycine (CHPG) activates mGlu5, but not mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36, 265–267 (1997).

    Article  CAS  Google Scholar 

  35. Kawabata, S. et al. Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors. Nature 383, 89–92 (1996).

    Article  CAS  Google Scholar 

  36. Mulkey, R. M., Herron, C. E. & Malenka, R. C. An essential role for protein phosphatases in hippocampal long-term depression. Science 261, 1051–1055 (1993).

    Article  CAS  Google Scholar 

  37. Mulkey, R. M., Endo, S., Shenolikar, S. & Malenka, R. C. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369, 486–488 (1994).

    Article  CAS  Google Scholar 

  38. Roberson, E. D., English, J. D. & Sweatt, J. D. A biochemist's view of long-term potentiation. Learn. Mem. 3, 1–4 (1996).

    Article  CAS  Google Scholar 

  39. Lisman, J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc. Natl. Acad. Sci. USA 86, 9574–9578 (1989).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank N. F. Ciliax, J. F. Paré, S. Risso Bradley and G. W. Hubert for their technical assistance. We also thank J. P. Pin for supplying the original mGluR5a construct. We would also like to acknowledge Dr. G. Pavlath and Fujisawa USA, Inc. for providing the FK506. This work was supported by NIH NINDS grants (S. A. and P. J. C.).

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Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    S. Alagarsamy, M. J. Marino, S. T. Rouse & P. J. Conn

  2. Division of Neuroscience, Baylor College of Medicine, Houston, 77030, Texas, USA

    R.W. Gereau IV

  3. Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    S. F. Heinemann

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  1. S. Alagarsamy
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Correspondence to P. J. Conn.

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Alagarsamy, S., Marino, M., Rouse, S. et al. Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat Neurosci 2, 234–240 (1999). https://doi.org/10.1038/6338

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