Abstract
In both excitable and non-excitable cells, calcium (Ca(2+)) signals are maintained by a highly integrated process involving store-operated Ca(2+) entry (SOCE), namely the opening of plasma membrane (PM) Ca(2+) channels following the release of Ca(2+) from intracellular stores. Upon depletion of Ca(2+) store, the stromal interaction molecule (STIM) senses Ca(2+) level reduction and migrates from endoplasmic reticulum (ER)-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC) prompting Ca(2+) refilling. Accumulating evidence suggests that SOCE dysregulation may trigger perturbation of intracellular Ca(2+) signaling in neurons, glia or hematopoietic cells, thus participating to the pathogenesis of diverse neurodegenerative diseases. Under acute conditions, such as ischemic stroke, neuronal SOCE can either re-establish Ca(2+) homeostasis or mediate Ca(2+) overload, thus providing a non-excitotoxic mechanism of ischemic neuronal death. The dualistic role of SOCE in brain ischemia is further underscored by the evidence that it also participates to endothelial restoration and to the stabilization of intravascular thrombi. In Parkinson's disease (PD) models, loss of SOCE triggers ER stress and dysfunction/degeneration of dopaminergic neurons. Disruption of neuronal SOCE also underlies Alzheimer's disease (AD) pathogenesis, since both in genetic mouse models and in human sporadic AD brain samples, reduced SOCE contributes to synaptic loss and cognitive decline. Unlike the AD setting, in the striatum from Huntington's disease (HD) transgenic mice, an increased STIM2 expression causes elevated synaptic SOCE that was suggested to underlie synaptic loss in medium spiny neurons. Thus, pharmacological inhibition of SOCE is beneficial to synapse maintenance in HD models, whereas the same approach may be anticipated to be detrimental to cortical and hippocampal pyramidal neurons. On the other hand, up-regulation of SOCE may be beneficial during AD. These intriguing findings highlight the importance of further mechanistic studies to dissect the molecular pathways, and their corresponding targets, involved in synaptic dysfunction and neuronal loss during aging and neurodegenerative diseases.