Src family tyrosine kinases (SFKs) upregulate the function of NMDA (N-methyl-D-aspartate) receptors (NMDARs) and act as a molecular hub on which various signalling pathways converge. The catalytic activity of SFKs is tightly controlled, mainly through intramolecular interactions and through phosphorylation and dephosphorylation of SFKs. SFKs can be activated by various protein tyrosine phosphatases (PTPs) or by extrinsic ligands that disrupt the intramolecular interactions.
There is extensive evidence that SFKs increase NMDAR channel gating without altering NMDAR single-channel conductance. Specific inhibitors have implicated Src in the upregulation of NMDAR function, but it is unclear whether other SFKs are involved in this regulation in vivo. The upregulation of NMDAR function by SFKs is opposed by the STEP61 isoform of the striatal enriched tyrosine phosphatase (STEP) family.
The NR2B subunit of the NMDAR is the main tyrosine-phosphorylated protein in the postsynaptic density, and the NR2A subunit is also phosphorylated on tyrosine. Both of these subunits have long, intracellular carboxy (C)-terminal tails with 25 tyrosine residues on each. It is unclear which residues undergo phosphorylation to mediate the effects of SFKs on NMDAR function.
SFK-mediated phosphorylation of NR2 subunits might also be involved in the increase in NMDAR levels at the synaptic membrane that follows tetanic stimulation. Phosphorylation of the C-terminal tails might interfere with the internalization of the receptors.
Signalling pathways that converge on the SFKs to influence NMDAR function include G-protein-coupled receptors, receptor protein tyrosine kinase signalling, the Ras pathway, and the cytokine receptor and integrin pathways.
NMDARs are crucial for several types of long-term plasticity in the CNS, such as long-term potentiation (LTP). SFKs are necessary for the induction of LTP in area CA1 of the hippocampus. A model is proposed in which tetanic stimulation activates CAKβ, which activates Src and allows tonic suppression of NMDAR function by STEP to be overcome. The resulting boost in the influx of Ca2+ is coupled with the reduction of the Mg2+ block by depolarization to set in motion the cascade that leads to potentiation at the synapse.
NMDARs have also been implicated in less desirable forms of plasticity, including those involved in chronic pain and epilepsy. The modulation of NMDARs by SFKs is likely to be involved in these functions as well.
Cerebral ischaemia also seems to involve NMDARs, and SFK signalling is increased in transient ischaemia, along with the phosphorylation of NR2 subunits. Furthermore, SFK-mediated NMDAR phosphorylation has also been implicated in neurodegeneration in Huntington's disease. The involvement of SFKs in these and other pathological processes should be investigated further.
In the central nervous system, synaptic strength is regulated partly by changes in the function and number of postsynaptic glutamate receptors. The NMDA (N-methyl-D-aspartate) subtype of glutamate receptor (NMDAR) is regulated in part by the opposing actions of protein tyrosine kinases and phosphotyrosine phosphatases. Members of the Src family of protein tyrosine kinases upregulate NMDAR function, thereby gating the production of NMDAR-dependent synaptic potentiation. Src family kinases (SFKs) are a crucial point of convergence for signalling pathways that enhance NMDAR activity, so that SFKs act as a molecular hub for the control of NMDARs. These kinases regulate synaptic strength and are therefore vital for processes that underlie physiological and pathological plasticity in the brain and spinal cord.
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The work of the authors is supported by the Canadian Institutes of Health Research (CIHR). M.W.S. is a member of the CIHR group on 'The Synapse'.
The authors declare no competing financial interests.
- G-PROTEIN-COUPLED RECEPTORS
(GPCRs). A large family of receptors that couple to second-messenger generation through multiple heterotrimeric G-proteins, consisting of Gα and Gβγ subunits. Members of this receptor family are grouped according to the G-protein subtypes to which they are coupled and include Gs-, Gq- and Gi-coupled receptors.
A covalent protein modification in which myristate, a 14-carbon saturated fatty acid, is added to N-terminal glycine. Fatty acid modifications, including myristoylation, palmitoylation and prenylation, increase protein hydrophobicity and facilitate interactions with lipid bilayers.
A post-translational modification of proteins in which palmitate, a 16-carbon saturated fatty acid, is added to a cysteine residue. Unlike other lipid modifications such as myristoylation and prenylation, palmitoylation is reversible.
- POSTSYNAPTIC DENSITY
(PSD). A primary structural component of excitatory synapses, first identified morphologically as an electron-dense intracellular structure adjacent to the postsynaptic membrane at excitatory synapses. Subsequently, biochemical methods were developed for the isolation and purification of a PSD fraction from the brain.
- LONG-TERM POTENTIATION
A persistent enhancement in the efficacy of synaptic transmission that is considered to be a model of learning and memory.
- CLATHRIN-MEDIATED ENDOCYTOSIS
A mode of vesicular transport that is involved in the internalization and recycling of receptors by clathrin-coated endocytic vesicles. The main components of the endocytic clathrin coats are the adaptor protein complex AP2 and clathrin.
An increased sensitivity to pain in which noxious stimuli evoke a greater and more prolonged pain.
A model of epilepsy in which repeated electrical or chemical stimulation of limbic structures, such as the amygdala or hippocampus, evokes progressively more severe electrical and behavioural responses, culminating in a generalized seizure. The kindled state is highly stable and can persist for months to years.
- HUNTINGTON'S DISEASE
A late-onset, autosomal-dominant neurodegenerative disorder that is characterized by abnormalities of movement and dementia. The mutation that underlies Huntington's disease is a CAG/polyglutamine repeat expansion in the gene that encodes the huntingtin protein.
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Salter, M., Kalia, L. Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 5, 317–328 (2004). https://doi.org/10.1038/nrn1368
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