Dependence of vital cell function on endoplasmic reticulum calcium levels: implications for the mechanisms underlying neuronal cell injury in different pathological states.

The endoplasmic reticulum (ER) is a subcellular compartment playing a pivotal role in the control of vital calcium-related cell functions, including calcium storage and signalling. In addition, newly synthesized membrane and secretory proteins are folded and processed in the ER, reactions which are strictly calcium dependent. The ER calcium activity is therefore high, being several orders of magnitude above that of the cytoplasm. Depletion of ER calcium stores causes an accumulation of unfolded proteins in the ER lumen, a pathological situation which induces the activation of two highly conserved stress responses, the ER overload response (EOR) and the unfolded protein response (UPR). EOR triggers activation of the transcription factor NF kappa B, which, in turn, activates the expression of target genes. UPR triggers two downstream processes: it activates the expression of genes coding for ER-resident stress proteins, and it causes a suppression of the initiation of protein synthesis. A similar stress response is activated in pathological states of the brain including cerebral ischaemia, implying common underlying mechanisms. Depending on the extent and duration of the disturbance, an isolated impairment of ER function is sufficient to induce cell injury. In this review, evidence is presented that ER function is indeed disturbed in various diseases of the brain, including acute pathological states (e.g. cerebral ischaemia) and degenerative diseases (e.g. Alzheimer's disease). A body of evidence suggests that disturbances of ER function could be a global pathomechanism underlying neuronal cell injury in various acute and chronic disorders of the central nervous system. If that is true, restoration of ER function or attenuation of secondary disturbances induced by ER dysfunction could present a highly promising new avenue for pharmacological intervention to minimize neuronal cell injury in different pathological states of the brain.