Metabotropic glutamate mGlu5 receptor-mediated serine phosphorylation of NMDA receptor subunit NR1 in hippocampal CA1 region after transient global ischemia in rats.
Phosphorylation of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the regulation of the receptor's ion channel. The contribution of metabotropic glutamate receptors to the NMDA receptor function after brain ischemia remains to be determined. Presently we investigated the effects of an antagonist of the metabotropic glutamate mGlu5 receptor on cell death and serine phosphorylation of the NR1 subunit of the NMDA receptor in the hippocampal CA1 region after transient global ischemia and sought to explore the mechanisms involved. Phosphorylation of serine residues at 890 and 896 of NR1 was increased predominantly in the deoxycholate (DOC)-insoluble fraction after transient global ischemia in rats; and the increase in the phosphorylation of S890, but not that of S896, of NR1 in this fraction was attenuated by the mGlu5 receptor antagonist. The administration of this antagonist also reduced the increase in the amount of protein kinase C (PKC)gamma, but not that of PKCalpha, in the DOC-insoluble fraction. The results suggest that the mGlu5 receptor in the hippocampal CA1 region is involved in the phosphorylation of S890 of NR1 subunit via PKCgamma following transient ischemia. As treatment with the mGlu5 receptor antagonist reduced cell death in the hippocampal CA1 region on day 3 after the start of the reperfusion, these changes in intracellular signaling through mGlu5 receptor may be linked to the pathogenesis of cerebral ischemia.
Takagi
Norio
N
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. takagino@ps.toyaku.ac.jp
Besshoh
Shintaro
S
Morita
Hirotsugu
H
Terao
Mihoko
M
Takeo
Satoshi
S
Tanonaka
Kouichi
K
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction
C409466:NR1 NMDA receptor; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; C121465:6-methyl-2-(phenylethynyl)pyridine; C087857:protein kinase C gamma; D011493:Protein Kinase C