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Oestrogen receptor subtype‐specific repression of calpain expression and calpain enzymatic activity in neuronal cells – implications for neuroprotection against Ca 2+ ‐mediated excitotoxicity
Author(s) -
Gamerdinger Martin,
Manthey Dieter,
Behl Christian
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03675.x
Subject(s) - calpain , calpastatin , neuroprotection , ionomycin , estrogen receptor , excitotoxicity , microbiology and biotechnology , receptor , biology , proteases , chemistry , endocrinology , medicine , nmda receptor , pharmacology , biochemistry , enzyme , intracellular , cancer , breast cancer
Calpains represent a superfamily of Ca 2+ ‐activated cysteine‐proteases, which are important mediators of apoptosis and necrosis. In the brain, m‐calpain and µ‐calpain, the two ubiquitous calpain‐isoforms, are strongly activated in neurones after an excitotoxic Ca 2+ influx occurring, for example, during cerebral ischemia. Because oestrogen and its receptors (ERα/ERβ) can exert neuroprotective activity, we investigated their influence on expression of calpains and their endogenous inhibitor, calpastatin. We found that ectopic expression of ERα in human neuroblastoma SK‐N‐MC cells led to a ligand‐independent constitutive down‐regulation of m‐calpain accompanied by an up‐regulation of µ‐calpain expression. Up‐regulation of µ‐calpain was reversed in the presence of oestrogen, which, in turn, could be blocked by co‐treatment with the oestrogen‐receptor antagonist ICI 182 780. Expression of calpastatin was not altered, either in the absence or in the presence of oestrogen. Additional studies revealed that ERα‐expressing cells exhibited decreased calpain enzymatic activity and increased survival when cells were exposed to the Ca 2+ ionophore, ionomycin. Since all investigated effects could be observed exclusively in the presence of ERα, but not ERβ, and since the effects are reduced when ERα and ERβ are co‐expressed, our data suggest a novel ER subtype‐specific neuroprotective action by repressing calpain expression and calpain activity under conditions of a massive Ca 2+ influx.