Abstract
The spatial and temporal regulation of cellular calcium signals is modulated via two main Ca2+ entry routes. Voltage-gated Ca2+ channels (VGCC) and Ca2+-release activated channels (CRAC) enable Ca2+ flow into electrically excitable and non-excitable cells, respectively. VGCC are well characterized transducers of electrical activity that allow Ca2+ signaling into the cell in response to action potentials or subthreshold depolarizing stimuli. The identification of STromal Interaction Molecule (STIM) and Orai proteins has provided significant insights into the understanding of CRAC function and regulation. This review will summarize the current state of knowledge of STIM-Orai interaction and their contribution to cellular Ca2+ handling mechanisms. We will then discuss the bidirectional actions of STIM1 on VGCC and CRAC. In contrast to the stimulatory role of STIM1 on Orai channel activity that facilitates Ca2+ entry, recent reports indicated the ability of STIM1 to suppress VGCC activity. This new concept changes our traditional understanding of Ca2+ handling mechanisms and highlights the existence of dynamically regulated signaling complexes of surface expressed ion channels and intracellular store membrane-embedded Ca2+ sensors. Overall, STIM1 is emerging as a new class of regulatory proteins that fine-tunes Ca2+ entry in response to endoplasmic/sarcoplasmic reticulum stress.
Highlights
This review will summarize the current state of knowledge of STromal Interaction Molecule (STIM)-Orai interaction and their contribution to cellular Ca2+ handling mechanisms
The interaction of STromal Interaction Molecule 1 (STIM1) with Ca2+-release activated channels (CRAC) or voltage-gated Ca2+ channels (VGCC) extends our understanding of the role of STIM1 in cellular Ca2+ handling
Distinct from its role as an endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) Ca2+ sensor to facilitate Ca2+ entry and replenish the stores, STIM1 suppresses the activity of voltage-gated Ca2+ channel in excitable cells
Summary
STIM1-mediated bidirectional regulation of Ca2+ entry through voltage-gated calcium channels (VGCC) and calcium-release activated channels (CRAC). In contrast to the stimulatory role of STIM1 on Orai channel activity that facilitates Ca2+ entry, recent reports indicated the ability of STIM1 to suppress VGCC activity This new concept changes our traditional understanding of Ca2+ handling mechanisms and highlights the existence of dynamically regulated signaling complexes of surface expressed ion channels and intracellular store membrane-embedded Ca2+ sensors. It has been recognized that Ca2+ influx into neuronal subcellular compartments (e.g., dendrites, somata, spines, axons) is mediated by two principal means of Ca2+ entry These routes are voltage-gated Ca2+ channels (VGCC) and ionotropic neurotransmitter receptors (Berridge, 1998; Catterall, 2011), both routes elicit crucial rises in cytosolic Ca2+ in response to different stimuli. Neurons along with other cell types display an Frontiers in Cellular Neuroscience www.frontiersin.org
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