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Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition

Nature Neuroscience volume 1, pages 185–191 (1998)Cite this article

Abstract

Activation of the tyrosine kinase Src potentiates NMDA-receptor currents, which is thought to be necessary for induction of hippocampal long-term potentiation. Although the carboxy(C)-terminal domain of the NR2A subunit contains potential tyrosine phosphorylation sites, the mechanism by which Src modulates synaptic plasticity and NMDA receptor currents is not fully understood. Here we present evidence from NR1 mutants and splice variants that Src potentiates NMDA-receptor currents by reducing the tonic inhibition of receptors composed of NR1 and NR2A subunits by extracellular zinc. Using site-directed mutagenesis, we have identified three C-terminal tyrosine residues of NR2A that are required for Src's modulation of the zinc sensitivity of NMDA receptors. Our data link two modulatory sites of NMDA receptors that were previously thought to be independent.

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Figure 1: Src potentiates NR1/NR2A receptors by reducing tonic zinc inhibition.
Figure 2: Src shifts IC50 for the voltage-independent zinc site of NR1/NR2A receptors.
Figure 3: Potentiation of NMDA-receptor currents by Src correlates with the amount of tonic inhibition of NR1/NR2A receptors by zinc.
Figure 4: Point mutations of tyrosine residues in NR2A C-terminal block Src's potentiation of NR1/NR2A currents and relief of zinc inhibition.
Figure 5: EDTA and Src increase the time constant of the slower component of NMDA currents.
Figure 6: Src reduces zinc sensitivity of NR1/NR2B receptors.

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Acknowledgements

We thank S.F.Heinemann for NR1 and NR2B cDNAs, N. Nakanishi for NR2A cDNA and M. Chalfie, M. Mayer and P. Seeburg for green fluorescent protein plasmid. We also thank P. Ascher, J. Neyton and I. Mody for critically reading the manuscript.

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Authors and Affiliations

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

    F. Zheng, M.B. Gingrich, S.F. Traynelis & P.J. Conn

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  1. F. Zheng
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  2. M.B. Gingrich
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  3. S.F. Traynelis
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  4. P.J. Conn
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Correspondence to F. Zheng.

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Zheng, F., Gingrich, M., Traynelis, S. et al. Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition. Nat Neurosci 1, 185–191 (1998). https://doi.org/10.1038/634

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