CommentariesSrc, N-methyl-d-aspartate (NMDA) receptors, and synaptic plasticity
Section snippets
Src in the CNS
PTKs fall into two main groups: receptor and non-receptor PTKs 9, 10. Receptor PTKs have a single transmembrane and intracellular region that often contains more than one copy of the catalytic domain. These PTKs are activated by the binding of signalling molecules, such as growth factors 11, 12, to the receptor site in the extracellular domain. In contrast, non-receptor or cytoplasmic PTKs are not directly activated by extracellular ligands. Non-receptor PTKs are intracellular proteins with one
Regulation of NMDA receptors by src
The NMDA receptor, as a main subtype of glutamate receptor, participates in rapid excitatory synaptic transmission throughout the CNS [29]. NMDA receptors are members of the superfamily of ligand-gated ion channels, and molecular cloning has led to the identification of a variety of NMDA receptor subunit proteins (NR1, NR2A–D, NR-L/χ1) 30, 31. Native NMDA receptors appear to be heteroligomeric complexes with the M2 region of the subunits coming together as a central pore selectively permeable
What is the molecular mechanism for the src-induced increase in NMDA channel gating?
This question subsumes two related but distinct issues. The first issue is determining which protein is the molecular target of the phosphorylation, and the second is understanding how it is that phosphorylation of a particular tyrosine residue(s) in that protein is transduced into the alteration in NMDA channel function. Before considering the potential molecular target, we note that it is conceivable that either intracellular or extracellular tyrosine residues might be subject to
What are the functional consequences of the regulation of NMDA receptors by Src?
By regulating the activity of post-synaptic NMDA receptors, tyrosine phosphorylation/dephosphorylation has the potential to modulate the efficacy of synaptic transmission. Because NMDA receptors are widely present at central synapses, there is the possibility that tyrosine phosphorylation could affect synaptic efficacy throughout the CNS. One region where Src is highly expressed is the CA1 region of the hippocampus [25]. Thus, we have examined the functional consequences of NMDA receptor
Summary
Src has been identified as an endogenous PTK that enhances the function of NMDA channels in CNS neurons. Current evidence is inconclusive as to whether the enhancement of function may be due to tyrosine phosphorylation of an NMDA receptor subunit protein or of an associated protein. A physiological consequence of the enhancement of NMDA channel function is that Src mediates induction of LTP in the CA1 region of the hippocampus. Src is expressed in various regions of the CNS [25], and in other
Acknowledgements
Work of the author is supported by the Medical Research Council of Canada and the Nicole Fealdman Memorial Fund. Thanks to Xian-Min Yu, Yueqiao Huang, and Jeff Gingrich for helpful comments on the manuscript.
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