Abstract
In both excitable and non-excitable cells, calcium (Ca2+) signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE), namely the opening of plasma membrane (PM) Ca2+ channels following the release of Ca2+ from intracellular stores. Upon depletion of Ca2+ store, the stromal interaction molecule (STIM) senses Ca2+ 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 Ca2+ refilling. Accumulating evidence suggests that SOCE dysregulation may trigger perturbation of intracellular Ca2+ 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 Ca2+ homeostasis or mediate Ca2+ 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.
Highlights
Calcium (Ca2+) is a ubiquitous second messenger involved in a number of cellular functions
In both excitable and non-excitable cells, including those involved in the immune response, Ca2+ signals are generated by storeoperated Ca2+entry (SOCE), namely the opening of plasma membrane (PM) Ca2+ channels following the release of Ca2+ from intracellular stores
The experimental evidence reviewed in the present work clearly demonstrates that Ca2+ homeostasis and, most notably, SOCE components are dysregulated in both acute and chronic neurodegenerative diseases
Summary
Calcium (Ca2+) is a ubiquitous second messenger involved in a number of cellular functions. Upon depletion of Ca2+ store, STIM senses Ca2+ level reduction and migrates from ER-like sites to the PM where it activates Orai (Zhang et al, 2005), a tetraspanning protein forming a ion-conducting pore highly selective for Ca2+ (Feske et al, 2006; Peinelt et al, 2006; Prakriya et al, 2006). This PM channel exists in three different forms, Orai, Orai and Orai exhibiting distinct inactivation and permeability properties (DeHaven et al, 2007; Lis et al, 2007). The present review mainly focusses on experimental data documenting the role of neuronal SOCE in neurodegenerative diseases, given the close interaction between the immune system and the brain during diverse pathological conditions (Amantea, 2016), the contribution of SOCE in immune cells could be envisaged and should deserve further investigation
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