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Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition
F Zheng1, M B Gingrich, S F Traynelis
1Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. fzheng@emory.edu
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 mechanisms 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.
Insights
The tyrosine kinase Src enhances NMDA-receptor currents by reducing zinc inhibition, crucial for synaptic plasticity. This study identifies specific NR2A tyrosine residues mediating Src
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Signaling
Background:
- Activation of the tyrosine kinase Src enhances NMDA-receptor currents, a process vital for hippocampal long-term potentiation.
- The carboxy-terminal domain of the NR2A subunit has potential tyrosine phosphorylation sites, but Src's precise mechanism in modulating synaptic plasticity and NMDA receptor currents remains unclear.
Purpose of the Study:
- To elucidate the mechanisms by which Src potentiates NMDA-receptor currents.
- To investigate the role of extracellular zinc in Src-mediated modulation of NMDA receptors.
- To identify specific tyrosine residues in the NR2A subunit critical for Src's action.
Main Methods:
- Utilized NR1 mutants and splice variants to study Src's effect on NMDA-receptor currents.
- Employed site-directed mutagenesis to identify key tyrosine residues in the NR2A subunit.
- Assessed the modulation of zinc sensitivity in NMDA receptors.
Main Results:
- Src potentiates NMDA-receptor currents by decreasing the inhibitory effect of extracellular zinc on NR1-NR2A receptors.
- Identified three C-terminal tyrosine residues on the NR2A subunit essential for Src's modulation of NMDA receptor zinc sensitivity.
- Demonstrated a functional link between two previously independent modulatory sites on NMDA receptors.
Conclusions:
- Src's potentiation of NMDA-receptor currents is mediated by a reduction in zinc inhibition.
- Specific tyrosine residues on NR2A are critical for Src-dependent regulation of NMDA receptor function.
- This research integrates distinct mechanisms of NMDA receptor modulation, advancing our understanding of synaptic plasticity.