Lithium reduced N-methyl-D-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia.
Recently, the neuroprotective effects of lithium against excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors have been demonstrated. Since brain ischemia results in NMDA receptor over-excitation and Src family protein tyrosine kinase-mediated tyrosine phosphorylation of NMDA receptor subunit 2A (NR2A) enhances NMDA receptor activity, we examined the effects of lithium on tyrosine phosphorylation of NR2A and its interactions with Src and Fyn (two members of the Src family of protein tyrosine kinases) mediated by PSD-95 (postsynaptic density protein 95 kDa) after 6 h of reperfusion following 15 min of ischemia (I/R), which was induced by occlusion of the four vessels in Sprague-Dawley rats. After abdominal injection of LiCl (2 mg/kg) for 7 days, the data showed that together with the significant decrease in I/R-induced tyrosine phosphorylation of NR2A, the interactions of NR2A with Src and Fyn mediated by PSD-95 were also decreased significantly. However, lithium pretreatment did not alter the total protein levels of NR2A, Src, Fyn and PSD-95. These results suggest that the inhibition of NR2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 may contribute to the lithium-induced downregulation of NMDA receptor function and provide neuroprotection against excitotoxicity.
Ma
Juan
J
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, 221002 Jiangsu, PR China.
Zhang
Guang-Yi
GY
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008094:Lithium; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051076:Proto-Oncogene Proteins c-fyn; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D019061:src-Family Kinases; C501449:Dlg4 protein, rat; C033652:postsynaptic density proteins; C494961:Fyn protein, rat