Oestrogen receptor subtype-specific repression of calpain expression and calpain enzymatic activity in neuronal cells--implications for neuroprotection against Ca-mediated excitotoxicity.
Calpains represent a superfamily of Ca2+-activated cysteine-proteases, which are important mediators of apoptosis and necrosis. In the brain, m-calpain and micro-calpain, the two ubiquitous calpain-isoforms, are strongly activated in neurones after an excitotoxic Ca2+ influx occurring, for example, during cerebral ischemia. Because oestrogen and its receptors (ERalpha/ERbeta) can exert neuroprotective activity, we investigated their influence on expression of calpains and their endogenous inhibitor, calpastatin. We found that ectopic expression of ERalpha in human neuroblastoma SK-N-MC cells led to a ligand-independent constitutive down-regulation of m-calpain accompanied by an up-regulation of micro-calpain expression. Up-regulation of micro-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 ERalpha-expressing cells exhibited decreased calpain enzymatic activity and increased survival when cells were exposed to the Ca2+ ionophore, ionomycin. Since all investigated effects could be observed exclusively in the presence of ERalpha, but not ERbeta, and since the effects are reduced when ERalpha and ERbeta 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 Ca2+ influx.
Gamerdinger
Martin
M
Department of Pathobiochemistry, Medical School, Johannes Gutenberg University, Mainz, Germany.
Manthey
Dieter
D
Behl
Christian
C
D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000633:toxicity*; D002154:Calpain / Q000378:metabolism*; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D020033:Protein Isoforms / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018696:Neuroprotective Agents; D009498:Neurotoxins; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D015759:Ionomycin; D002154:Calpain; D002118:Calcium