title: Cross-talk of intracellular calcium stores in the response to neuronal ischemia and ischemic tolerance.
abstract: Ischemic/reperfusion brain injury (IRI) is a very severe event with the multiple etiopathogenesis. Ischemic preconditioning (IPC) is an important phenomenon of adaptation of CNS to subsequent ischemia. An altered cross-talk between intracellular calcium stores is presumed in the mechanisms of ischemic damage/protection. We show here that IRI leads to the inhibition of mitochondrial respiratory complexes I and IV, however due to the excess of their capacities, the mitochondrial Ca(2+) uptake rate is not significantly depressed. IPC acts at the level of both initiation and execution of IRI-induced mitochondrial apoptosis and protects from IRI-associated changes in integrity of mitochondrial membranes. IPC also activates inhibition of p53 translocation to mitochondria. Inhibition of the mitochondrial p53 pathway might thus provide a potentially important mechanism of neuronal survival after ischemic brain damage. In addition, IRI initiates a time dependent differences in endoplasmic reticular (ER) gene expression of the key UPR proteins at both the mRNA and protein levels. Moreover, gene expression of the UPR proteins is affected by preischemic treatment by the increased expression of Ca(2+) binding protein: GRP 78 and transcriptional factor ATF6 in reperfusion times. Thus, IPC exerts a role in the attenuation of ER stress response, which might be involved in the neuroprotective phenomenon of ischemic tolerance. Hippocampal cells respond to the IRI by the specific expression pattern of the secretory pathways Ca(2+) pump (SPCA1) and this pattern is affected by preischemic challenge. IPC also incompletely suppresses lipo- and protein oxidation of hippocampal membranes and leads to partial recovery of the ischemic-induced depression of SPCA activity. The data suggests the correlation of SPCA function with the role of secretory pathways (Golgi apparatus) in response to preischemic challenge. Documented functional alterations of mitochondria, ER and Golgi apparatus put light into the understanding of cross-talk between intracellular Ca(2+) stores in cerebral ischemia and ischemic tolerance and might suggest for possible targets of future therapeutic interventions to enhance recovery after stroke.
authors.affiliation: Department of Medical Biochemistry, Comenius University, Jessenius Faculty of Medicine, SK-03601, Martin, Slovakia. lehotsky@jfmed.uniba.sk
authors.forename: Ján
authors.initials: J
authors.lastname: Lehotský
authors.forename: Peter
authors.initials: P
authors.lastname: Racay
authors.forename: Martina
authors.initials: M
authors.lastname: Pavlíková
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tatarková
authors.forename: Peter
authors.initials: P
authors.lastname: Urban
authors.forename: Mária
authors.initials: M
authors.lastname: Chomová
authors.forename: Mária
authors.initials: M
authors.lastname: Kovalská
authors.forename: Peter
authors.initials: P
authors.lastname: Kaplán
mesh_terms: D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C492023:Atp2c1 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium