On the role of store-operated calcium entry in acute and chronic neurodegenerative diseases
- 1Division of Pharmacology Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Italy
- 2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Italy
In both excitable and non-excitable cells, Ca2+ signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE), namely the opening of plasma membrane 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 plasma membrane 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+ signalling 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 mediates 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 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.
Keywords: Alzheimer’s disease, Endoplasmic Reticulum, Orai, Parkinson’s disease, SOCE, STIM, Stroke, TRPC
Received: 08 Jan 2018;
Accepted: 06 Mar 2018.
Edited by:Wendy Noble, King's College London, United Kingdom
Reviewed by:Sonal Srikanth, University of California, Los Angeles, United States
JUAN A. ROSADO DIONISIO, Universidad de Extremadura, Spain
Copyright: © 2018 Secondo, Bagetta and Amantea. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Prof. Agnese Secondo, University of Naples Federico II, Division of Pharmacology Department of Neuroscience, Reproductive and Odontostomatological Sciences, Napoli, Italy, email@example.com
Prof. Diana Amantea, University of Calabria, Department of Pharmacy, Health and Nutritional Sciences, via Savinio, Ed. Polifunzionale, Cosenza, I-87036, CS, Italy, firstname.lastname@example.org