Tyrosine NMDA receptors

Hallett, P. J., Spoelgen, R., Hyman, B. T., Standaert, D. G. and Dunah, A. W. (2006). Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J. Neurosci. 26, 4690-700. 

Fig. 16.11. Model of the association of Fyn kinase with the NMDA receptor The NMDA receptor is shown as a tetramer of NRl and NR2 subunits. The C-terminal tail of NR2 interacts with PDZ2 of PSD-95. The protein tyrosine kinase Fyn is assumed to bind to PDZ3 of PSD-95 via its SH2 domain. Fyn also is anchored to the ceU membrane via its myristoylated N-terminus. GK guanylate kinase domain of PSD-95. According to Sala and Sheng (1999), with permission.

Like many other ligand-gated ion chaimels, the charmel gating properties of the NMDA receptor are regulated by phosphorylation. The NR2 subimit of the receptor contains many Tyr phosphorylation sites in the cytoplasmic region and it has been shown that receptor activity is stimulated by Tyr phosphorylation. Cytoplasmic nonreceptor tyrosine kinases of the Src family are responsible for the Tyr phosphorylation. Thus, a specific association with PSD-95, and thereby mediation of phosphorylation of NR2, has been demonstrated for the Fyn kinase, a member of the Src kinase family (Tezuka et al., 1999). Thus, the nonreceptor tyrosine kinase has an important role in regulation of synaptic activity and plasticity. A model for Fyn association with the NMDA receptor/PSD95 complex is shown in Fig. 16.11. 

Another mechanism of synaptic dysfunction in AD may involve amyloid ft peptide (Aft a 40 to 42 amino acid peptide). A marked increase in Aft levels occurs in brain tissue from AD patients. A ft inhibits glutamatergic neurotransmission and reduces synaptic plasticity (Snyder et al., 2005). Treatment of cortical neuronal cultures with Aft facilitates endocytosis of NMDA receptor. Aft-mediated endo-cytosis of NMDA receptor requires the a-1 nicotinic receptor, protein phosphatase 2B, and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyrl472 correlates with receptor endocytosis. The addition of a y-secretase inhibitor not only reduces Aft but also restores surface expression of NMDA receptors, suggesting that A plays an important role in the regulation of NMDA and AMPA receptor trafficking (Snyder et al., 2005 Morishita et al., 2005). 

Viviani B., Gardoni F., Bartesaghi S., Corsini E., Facchi A., Galli C. L., Di Luca M., and Marinovich M. (2006). Interleukin-1 released by gpl20 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors. J. Biol. Chem. 281 30212-30222. 

Bading, H., and Greenberg, M. E. (1991). Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253, 912-914. 

Zheng F, Gingrich MB, et al. 1998. Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition. Nat Neurosci 1 185-191. 

An emerging theme in cell biology is that protein kinases are often targeted to their substrates by association with specific anchoring proteins. Non-receptor tyrosine kinases of the Src family have been implicated in NMDA receptor modulation (Salter, 1998), and recent evidence suggests that Src family kinases may be components of the NMDA... 

Rump P, Zhang Y, Xu J et al (2010) Abeta-mediated NMDA receptor endocytosis in Alzheimer s disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci 30 5948-5957... 

These findings strongly support the notion that physiologically active PrPc is part of signaling cascades implicated in various cellular processes. Of note, GPI-anchored proteins like PrPc do not have direct contact with the cytosolic compartment and therefore require co-factors for intracellular signal transmission (reviewed in [115]). Attractive candidates for cellular components involved in PrPc-dependent signaling include NMDA receptors [106] and the intracellular tyrosine kinase Fyn [116, 117]. 

Fig. 2. Distribution of twelve large target-specific groups of pharmaceutical agents within the Kohonen map (a) G-protein-coupled receptors (GPCR) agonists/antagonists (5,432 compounds) (b) matrix metalloproteinase inhibitors (120 compounds) (c) tyrosine kinase inhibitors (175 compounds) (d) caspase inhibitors (50 compounds) (e) NMDA receptor agonists/antagonists (150 compounds) (f) potassium channel blockers/activators (302 compounds) ...

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