Calpastatin Is Up-regulated in Response to Hypoxia and Is a Suicide Substrate to Calpain after Neonatal Cerebral Hypoxia-Ischemia

In a model of cerebral hypoxia-ischemia in the immature rat, widespread brain injury is produced in the ipsilateral hemisphere, whereas the contralateral hemisphere is left undamaged. Previously, we found that calpains were equally translocated to cellular membranes (a prerequisite for protease acti...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-05, Vol.274 (20), p.14046-14052
Main Authors: Blomgren, Klas, Hallin, Ulrika, Andersson, Anna-Lena, Puka-Sundvall, Malgorzata, Bahr, Ben A., McRae, Amanda, Saido, Takaomi C., Kawashima, Seiichi, Hagberg, Henrik
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Brain - drug effects
Brain - enzymology
Brain - pathology
Brain Ischemia - metabolism
Calcium-Binding Proteins - metabolism
Calpain - metabolism
Cell Membrane - enzymology
Cysteine Proteinase Inhibitors - pharmacology
Dipeptides - pharmacology
Enzyme Activation
Female
Functional Laterality
Hypoxia - metabolism
Male
Rats
Rats, Wistar
Up-Regulation
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Summary:In a model of cerebral hypoxia-ischemia in the immature rat, widespread brain injury is produced in the ipsilateral hemisphere, whereas the contralateral hemisphere is left undamaged. Previously, we found that calpains were equally translocated to cellular membranes (a prerequisite for protease activation) in the ipsilateral and contralateral hemispheres. However, activation, as judged by degradation of fodrin, occurred only in the ipsilateral hemisphere. In this study we demonstrate that calpastatin, the specific, endogenous inhibitor protein to calpain, is up-regulated in response to hypoxia and may be responsible for the halted calpain activation in the contralateral hemisphere. Concomitantly, extensive degradation of calpastatin occurred in the ipsilateral hemisphere, as demonstrated by the appearance of a membrane-bound 50-kDa calpastatin breakdown product. The calpastatin breakdown product accumulated in the synaptosomal fraction, displaying a peak 24 h post-insult, but was not detectable in the cytosolic fraction. The degradation of calpastatin was blocked by administration of CX295, a calpain inhibitor, indicating that calpastatin acts as a suicide substrate to calpain during hypoxia-ischemia. In summary, calpastatin was up-regulated in areas that remain undamaged and degraded in areas where excessive activation of calpains and infarction occurs.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.20.14046