Lithium suppressed Tyr-402 phosphorylation of proline-rich tyrosine kinase (Pyk2) and interactions of Pyk2 and PSD-95 with NR2A in rat hippocampus following cerebral ischemia.
It has been indicated that Pyk2/Src signaling pathway is involved in modulation of N-methyl-D-aspartate-type (NMDA) glutamate receptor activity. Lithium protects against glutamate-induced excitotoxicity in cultured neurons and in animal models of diseases. The neuroprotection against excitotoxicity afforded by lithium is time-dependent, requiring treatment for 6-7 days for maximal effect. In this study, we examined the time-course and the effect of lithium on Tyr-402 phosphorylation of Pyk2 and Tyr-416 phosphorylation of Src as well as the association of Pyk2 and NMDA receptor subunit 2A (NR2A) mediated by postsynaptic density protein 95 kDa (PSD-95) in the condition of cerebral ischemia, which was induced by occlusion of the four vessels in Sprague-Dawley rats. At 6 h of reperfusion following 15 min of ischemia (I/R), the effects induced by chronic lithium were observed, including the decrease in enhanced Tyr-402 phosphorylation of Pyk2, the inhibition in increased Tyr-416 phosphorylation of Src and the attenuation in enhanced interactions of Pyk2 and PSD-95 with NR2A. Our results further suggest that the activated Pyk2 potentiates NMDA receptor function during transient brain ischemia followed by reperfusion and the above inhibition induced by lithium is likely to result in the inactivation of NMDA receptor and contributes to the neuroprotection against excitotoxicity.
Ma
Juan
J
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu 221002 PR China.
Zhang
Guang-Yi
GY
Liu
Yong
Y
Yan
Jing-Zhi
JZ
Hao
Zhi-Bin
ZB
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D051418:Focal Adhesion Kinase 2; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting / Q000379:methods; 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; D011233:Precipitin Tests / Q000379:methods; D011392:Proline; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D014443:Tyrosine; D011392:Proline; D008094:Lithium; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D019061:src-Family Kinases