Abstract
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. The ionotropic glutamate receptors are classified into two groups, NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors. The AMPA receptor is a ligand-gated cation channel that mediates the fast component of excitatory postsynaptic currents in the central nervous system1,2. Here we report that AMPA receptors function not only as ion channels but also as cell-surface signal transducers by means of their interaction with the Src-family non-receptor protein tyrosine kinase Lyn. In the cerebellum, Lyn is physically associated with the AMPA receptor and is rapidly activated following stimulation of the receptor. Activation of Lyn is independent of Ca2+ and Na+ influx through AMPA receptors. As a result of activation of Lyn, the mitogen-activated protein kinase (MAPK) signalling pathway is activated, and the expression of brain-derived neurotrophic factor (BDNF) messenger RNA is increased in a Lyn-kinase-dependent manner. Thus, AMPA receptors generate intracellular signals from the cell surface to the nucleus through the Lyn–MAPK pathway, which may contribute to synaptic plasticity by regulating the expression of BDNF.
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References
Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).
Sakimura, K. et al. Functional expression from cloned cDNAs of glutamate receptor species responsive to kainate and quisqualate. FEBS Lett. 272, 73–80 (1990).
Wagner, K. R., Mei, L. & Huganir, R. L. Protein tyrosine kinases and phosphatases in the nervous system. Curr. Opin. Neurobiol. 1, 65–73 (1991).
Umemori, H., Sato, S., Yagi, T., Aizawa, S. & Yamamoto, T. Initial events of myelination involve Fyn tyrosine kinase signalling. Nature 367, 572–576 (1994).
Sudol, M., Alvarez-Buylla, A. & Hanafusa, H. Differential developmental expression of cellular yes and cellular src proteins in cerebellum. Oncogene Res. 2, 345–355 (1988).
Grant, S. G. N. et al. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258, 1903–1910 (1992).
Umemori, H. et al. Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system. Mol. Brain Res. 16, 303–310 (1992).
Chen, S., Ren, Y. Q. & Hillman, D. E. Transient expression of lyn gene in Purkinje cells during cerebellar development. Dev. Brain Res. 92, 140–146 (1996).
Holmes, T. C., Fadool, D. A., Ren, R. & Levitan, I. B. Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain. Science 274, 2089–2091 (1996).
Yu, X.-M., Askalan, R., Keil, G. J. I & Salter, M. W. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275, 674–678 (1997).
Wenthold, R. J., Yokotani, N., Doi, K. & Wada, K. Immunochemical characterization of the non-NMDA glutamate receptor using subunit-specific antibodies. J. Biol. Chem. 267, 501–507 (1992).
Xu, W., Harrison, S. C. & Eck, M. J. Three-dimensional structure of the tyrosine kinase c-Src. Nature 385, 595–602 (1997).
Sicheri, F., Moarefi, I. & Kuriyan, J. Crystal structure of the Src family tyrosine kinase Hck. Nature 385, 602–609 (1997).
Fiore, R. S., Murphy, T. H., Sanghera, J. S., Pelech, S. L. & Baraban, J. M. Activation of p42 mitogen-activated protein kinase by glutamate receptor stimulation in rat primary cortical cultures. J. Neurochem. 61, 1626–1633 (1993).
Miyake, S. et al. Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and cosmid bearing the full-length virus genome. Proc. Natl Acad. Sci. USA 93, 1320–1324 (1996).
Le Gal La Salle, G. et al. An adenovirus vector for gene transfer into neurons and glia in the brain. Science 259, 988–990 (1993).
Treisman, R. Regulation of transcription by MAP kinase cascades. Curr. Opin. Cell Biol. 8, 205–215 (1996).
Thoenen, H. Neurotrophins and neuronal plasticity. Science 270, 593–598 (1995).
Lo, D. C. Neurotrophic factors and synaptic plasticity. Neuron 15, 979–981 (1995).
Zafra, F., Hengerer, B., Leibrock, J., Thoenen, H. & Lindholm, D. Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 9, 3545–3550 (1990).
Bessho, Y., Nakanishi, S. & Nawa, H. Glutamate receptor agonists enhance the expression of BDNF mRNA in cultured cerebellar granule cells. Mol. Brain Res. 18, 201–208 (1993).
O'Dell, T. J., Kandel, E. R. & Grant, S. G. N. Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors. Nature 353, 558–560 (1991).
Boxall, A. R., Lancaster, B. & Garthwaite, J. Tyrosine kinase is required for long-term depression in the cerebellum. Neuron 16, 805–813 (1996).
Kang, H. & Schuman, E. M. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267, 1658–1662 (1995).
Hirano, T., Kubo, Y. & Wu, M. M. Cerebellar granule cells in culture: monosynaptic connections with Purkinje cells and ionic currents. Proc. Natl Acad. Sci. USA 83, 4957–4961 (1986).
Yamanashi, Y., Kakiuchi, T., Mizuguchi, J., Yamamoto, T. & Toyosima, K. Association of B cell antigen receptor with protein tyrosine kinase Lyn. Science 251, 192–194 (1991).
Yamanashi, Y. et al. Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling. Proc. Natl Acad. Sci. USA 89, 1118–1122 (1992).
Wang, Y., Small, D. L., Stanimirovic, D. B., Morley, P. & Durkin, J. P. AMPA receptor-mediated regulation of a Gi-protein in cortical neurons. Nature 389, 502–504 (1997).
Acknowledgements
We thank T. Hirano, D. W. Saffen, Y. Hayashi, Y. W. Yamanashi and J. Inoue for valuable discussions; I. Saito and Y. Kanegae for preparation of recombinant adenovirus; H. Nawa for rat BDNF cDNA; and S. Nagasawa for care of mice. This work was supported by grants from the Ministry of Education, Science and Culture of Japan.
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Hayashi, T., Umemori, H., Mishina, M. et al. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature 397, 72–76 (1999). https://doi.org/10.1038/16269
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DOI: https://doi.org/10.1038/16269
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