Estrogen receptor subtype-specific repression of calpain-activation in neuronal cells

Calpains represent a superfamily of Ca²⁺-dependent cysteine-proteases which are important mediators of apoptosis and necrosis in different tissues. In the brain, these proteases are strongly activated in neurons, which are affected by an excitotoxic Ca²⁺ influx, e.g. during cerebral ischemia. Estrogen and its receptors (ERα/ERβ) are well-known neuroprotective mediators, which can suppress pathological processes. Here, we show that ectopic expression of ERα in human neuroblastoma SK-N-MC cells led to a ligand-independent suppression of calpain enzymatic activity and increased survival when cells were exposed to the Ca²⁺-ionophore ionomycin or to oxidative stress (e.g. H₂O₂). Further, we found that the transcriptional activity of genes encoding for the catalytic subunits of the calpain-isoforms µ- and m-calpain were significantly altered in the presence of ERα in SK-N-MC cells. Transcription of m-calpain was down-regulated, accompanied by an up-regulation of µ-calpain gene expression. Additional studies revealed no changes in the expression of the endogenous calpain-inhibitor calpastatin. Interestingly, diminished calpain-activation, altered calpain gene expression pattern and stress resistance are specifically mediated by ERα but not ERβ. In conclusion, we have shown for the first time an ERα-mediated intervention in apoptotic or necrotic processes by repressing calpain-activation presumably based on transcriptional regulation of µ- and m-calpain gene expression.