title: Persistent phosphorylation of synaptic proteins following middle cerebral artery occlusion.
abstract: Transient cerebral ischemia following 1 to 2 hours of middle cerebral artery occlusion (MCAO) in the rat leads to infarction, which can be diminished by synaptic transmission modulators, implying aberrant cell signaling in the pathogenetic process. The authors report here changes in the levels of tyrosine phosphorylated proteins (PTyr) and calcium calmodulin kinase II (CaMKII) phosphorylation of Thr 286, in synaptosomal, particulate, and cytosolic fractions of different cortical areas following 1 or 2 hours of MCAO, or 2 hours of MCAO followed by 2 hours of reperfusion. At the end of 2-hour MCAO, PTyr, and in particular the pp180, indicative of NR2A/B subunit, increased in the synaptosomal fraction in less ischemic areas while it decreased in more severe ischemic regions. During reperfusion, phosphorylation increased at least 2-fold in all reperfused areas. During 2 hours of MCAO, the phosphorylation of CaMKII increased 8- to 10-fold in the synaptosomal fraction in all ischemic brain regions. During reperfusion, the phospho-CaMKII levels remained elevated by approximately 300% compared with the contralateral hemisphere (control). There was no increase in phospho-CaMKII in the cytosolic fraction at any time during or following ischemia in any of the brain regions examined. The authors conclude that both tyrosine kinase coupled pathways, as well as CaMKII-mediated cellular processes associated with synaptic activity, are strongly activated during and particularly following MCAO. These results support the hypothesis that aberrant cell signaling may contribute to ischemic cell death and dysfunction, and that selective modulators of cell signaling may be targets for pharmacological intervention against ischemic brain damage.
authors.affiliation: Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University Hospital, Sweden. shohei@tokyo-med.ac.jp
authors.forename: Shohei
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.forename: Atsushi
authors.initials: A
authors.lastname: Isshiki
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002458:Cell Fractionation; D004195:Disease Models, Animal; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D020768:Middle Cerebral Artery; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D013569:Synapses / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors
chemical_list: D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases