NMDA receptors are critical mediators of long lasting changes in the efficacy of synaptic transmission (i.e. LTP and LTD). NMDA receptors are glutamate gated ion channels consisting of a dimer of NR1 subunits and hompdimer or heterodimer of NR2 subunits. One type of NR2 subunit, NR2B, is of particular interest due to its involvement in both synaptic plasticity and numerous neurological pathologies. NMDA receptors are upregulated by Src family kinase mediated tyrosine phosphorylation of NR2A and NR2B. One tyrosine residue of particular interest on NR2B is Tyr1472. Phosphorylation of Tyr1472 is believed to promote surface expression of NR2B containing NMDA receptors by blocking an association between NR2B and the clathrin adaptor protein AP-2. Increases in Tyr1472 phosphorylation are evident in status epilepticus, neuropathic pain, and following transient ischemia. Decreases in Tyr1472 phosphorylation have been observed in Alzheimer's disease. Src family kinases are activated in the post-synaptic density following activation of Pyk2. Pyk2 activation is dependent upon increases in intracellular Ca2+ and PKC activation. Pyk2's importance in synaptic function is underscored by the fact that Pyk2 is necessary for LTP in hippocampal neurons, and the observation that Pyk2 is upregulated following transient ischemia. We hypothesize Pyk2 is an important regulator of surface expression for NR2B containing NMDA receptors via activation of Src and/or Fyn. We propose to test our hypothesis by activating or inhibiting Pyk2 and assaying for changes in NR2B surface expression and Tyr1472 phosphorylation. In addition we will specifically inhibit Src or Fyn while activating Pyk2 and assay for changes in NR2B surface expression and Tyr1472 phosphorylation. Our results will demonstrate whether Pyk2 is important for regulating NR2B surface expression, thus making Pyk2 a potential therapeutic target in neurological disease. ? ? ?
| Ulrich, Jason D; Kim, Man-Su; Houlihan, Patrick R et al. (2012) Distinct activation properties of the nuclear factor of activated T-cells (NFAT) isoforms NFATc3 and NFATc4 in neurons. J Biol Chem 287:37594-609 |
| Bartos, Jason A; Ulrich, Jason D; Li, Hongbin et al. (2010) Postsynaptic clustering and activation of Pyk2 by PSD-95. J Neurosci 30:449-63 |
