Elsevier

Biochemical Pharmacology

Volume 56, Issue 7, 1 October 1998, Pages 789-798
Biochemical Pharmacology

Commentaries
Src, N-methyl-d-aspartate (NMDA) receptors, and synaptic plasticity

https://doi.org/10.1016/S0006-2952(98)00124-5Get rights and content

Abstract

The protein tyrosine kinase Src is expressed widely in the central nervous system and is abundant in neurons. Over the past several years, evidence has accumulated showing that one function of Src is to regulate the activity of N-methyl-d-aspartate (NMDA) receptors and other ion channels. NMDA receptors are a principal subtype of glutamate receptor that mediates fast excitatory transmission at most central synapses. Recently it has been discovered that, by means of up-regulating the function of NMDA receptors, Src mediates the induction of long-term potentiation (LTP) in the CA1 region of the hippocampus. This finding led to a new model for induction of LTP whereby tetanic stimulation produces a rapid activation of Src, causing enhanced NMDA receptor function. This enhanced NMDA receptor function boosts the entry of Ca2+, which may thereby trigger the downstream signalling cascade, ending in potentiation of non-NMDA receptors. This functional role for Src may be important in physiological and pathophysiological processes in the central nervous system.

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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