Abstract
Calcium (Ca2+) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca2+ channels and Ca2+ storage in various organelles is critical in maintaining cytosolic Ca2+ levels that provide the spatial resolution needed for cellular homeostasis. An important regulatory aspect of Ca2+ homeostasis is a store operated Ca2+ entry (SOCE) mechanism that is activated by the depletion of Ca2+ from internal ER stores and has gained much attention for influencing functions in both excitable and non-excitable cells. Ca2+ has been shown to regulate opposing functions such as autophagy, that promote cell survival; on the other hand, Ca2+ also regulates programmed cell death processes such as apoptosis. The functional significance of the TRP/Orai channels has been elaborately studied; however, information on how they can modulate opposing functions and modulate function in excitable and non-excitable cells is limited. Importantly, perturbations in SOCE have been implicated in a spectrum of pathological neurodegenerative conditions. The critical role of autophagy machinery in the pathogenesis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, would presumably unveil avenues for plausible therapeutic interventions for these diseases. We thus review the role of SOCE-regulated Ca2+ signaling in modulating these diverse functions in stem cell, immune regulation and neuromodulation.
Highlights
Calcium is a prominent regulator for diverse processes such as gene transcription, proliferation, cell motility, cell signaling, neuronal regulation, autophagy and apoptosis [1]
The rupture of outer mitochondrial membrane (OMM) activates the release of several pro-apoptotic proteins such as cytochrome c, apoptosis-inducing factor (AIF), procaspase 9, Smac/DIABLO, and endonuclease G into the cytosol, where it partners with other proteins and initiates the signaling cascade, leading to apoptosis [35,46,47,48,49]
Clearly, intracellular Ca2+ plays a crucial role in both basal and induced autophagy and in the regulation of apoptosis in both non-excitable and excitable cells
Summary
Calcium is a prominent regulator for diverse processes such as gene transcription, proliferation, cell motility, cell signaling, neuronal regulation, autophagy and apoptosis [1]. To perform such a broad spectrum of functions, the cells have evolved multiple unique mechanisms that are modulated by different proteins that regulate cellular Ca2+ levels. We review what is known about Ca2+-channel-induced Ca2+ signaling and how this fundamental second messenger regulates life and death decisions, with particular attention directed to cell autophagy in both excitable and non-excitable cells. Intracellular Ca2+ plays a crucial role in both basal and induced autophagy along with modulating apoptosis [5,6] (Figure 1A,B). The amount of releasable Ca2+—rather than the Ca2+ concentration of the ER— seems to be the relevant parameter for the transduction of the death signal, as it controls the ‘amplitude’ of the signal reaching the mitochondria [1,5,8,16,17,18]
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