MINI REVIEW ARTICLE published: 24 February 2014 CELLULAR NEUROSCIENCE doi: 10.3389/fncel.2014.00043 STIM1-mediated bidirectional regulation of Ca2+ entry through voltage-gated calcium channels (VGCC) and calcium-release activated channels (CRAC) Osama F. Harraz 1,2 and Christophe Altier 3* 1 Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt 3 Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Inflammation Research Network, University of Calgary, Calgary, AB, Canada Edited by: The spatial and temporal regulation of cellular calcium signals is modulated via two Leigh Anne Swayne, University of 2 2 2 main Ca C entry routes. Voltage-gated Ca C channels (VGCC) and Ca C-release activated Victoria, Canada 2 channels (CRAC) enable Ca C flow into electrically excitable and non-excitable cells, Reviewed by: respectively. VGCC are well characterized transducers of electrical activity that allow Francois Rassendren, Centre National 2 de la Recherche Scientifique, France Ca C signaling into the cell in response to action potentials or subthreshold depolarizing J. David Spafford, University of stimuli. The identification of STromal Interaction Molecule (STIM) and Orai proteins has Waterloo, Canada provided significant insights into the understanding of CRAC function and regulation. *Correspondence: This review will summarize the current state of knowledge of STIM-Orai interaction Christophe Altier, Department of and their contribution to cellular Ca2 handling mechanisms. We will then discuss the Physiology and Pharmacology, Snyder C Institute for Chronic Diseases, bidirectional actions of STIM1 on VGCC and CRAC. In contrast to the stimulatory role of 2 Inflammation Research Network, STIM1 on Orai channel activity that facilitates Ca C entry, recent reports indicated the University of Calgary, 3330 Hospital ability of STIM1 to suppress VGCC activity. This new concept changes our traditional Dr. NW, Calgary, AB T2N-4N1, Canada understanding of Ca2 handling mechanisms and highlights the existence of dynamically e-mail: [email protected] C regulated signaling complexes of surface expressed ion channels and intracellular store 2 membrane-embedded Ca C sensors. Overall, STIM1 is emerging as a new class of 2 regulatory proteins that fine-tunes Ca C entry in response to endoplasmic/sarcoplasmic reticulum stress. Keywords: STIM1, Orai, VGCC, CRAC, L-type, T-type, calcium channels, store-operated Ca2+ entry Ca2+ HANDLING MECHANISMS the cytoplasm) and reuptake (into the Ca2C store). The main C The second messenger calcium (Ca2C) plays a crucial role in a intracellular Ca2 stores are the endoplasmic reticulum (ER) and broad range of eukaryotic cellular functions. Regulation of its sarcoplasmic reticulum (SR). A number of regulatory mecha- 2C intracellular concentration ([Ca ]i) represents a major determi- nisms have been proposed to mediate the cellular influx, efflux, C C nant that controls signal transduction pathways such as secretion, release and reuptake of Ca2 , thus achieving Ca2 homeostasis excitation/contraction coupling, motility, transcription, growth, within the cell (Berridge et al., 2003; Stutzmann and Mattson, cell division or apoptosis (Berridge et al., 2003; Catterall, 2011). 2011). Accumulated data suggest that this homeostasis involves C C Precise neural circuit formation and control of neuronal excitabil- the concerted action of Ca2 entry channels at the PM and Ca2 ity necessitate the tight handling of Ca2C. Further, Ca2C signals release channels in intracellular ER/SR stores (Figure 1). C are crucial for synaptic transmission and plasticity (Berridge, Over the past decades, it has been recognized that Ca2 1998). In addition, pathophysiological neural insults such as influx into neuronal subcellular compartments (e.g., dendrites, cerebral ischemia can evoke an unwanted rise in Ca2C leading to somata, spines, axons) is mediated by two principal means C C Ca2C overload toxicity and neuronal cell death (Berridge, 1998; of Ca2 entry. These routes are voltage-gated Ca2 channels Arundine and Tymianski, 2004). (VGCC) and ionotropic neurotransmitter receptors (Berridge, Strict handling of intracellular Ca2C is necessary to maintain 1998; Catterall, 2011), both routes elicit crucial rises in cytosolic C optimized cellular functions. In general, Ca2C signals are mod- Ca2 in response to different stimuli. VGCC are widely expressed C ified by the control of Ca2C flux in (entry) and out (efflux) of in excitable cells and they trigger Ca2 influx over specific ranges the cell through plasma membrane (PM) channels and trans- of membrane potentials. Activation of VGCC generates fast porters that facilitate Ca2C movement between the extracellu- neurotransmission at nerve terminals (Bezprozvanny et al., 1995), lar milieu and cytoplasm across a Ca2C concentration gradient or excitation-contraction coupling in cardiac, skeletal and smooth (Berridge et al., 2003). In addition, integral proteins localized muscle cells (Catterall, 2011; Tuluc and Flucher, 2011; Navedo and in the membranes of intracellular stores allow Ca2C release (to Santana, 2013). Neurons along with other cell types display an Frontiers in Cellular Neuroscience www.frontiersin.org February 2014 | Volume 8 | Article 43 | 1 Harraz and Altier STIM1 inhibits VGCC 2C 2 FIGURE 1 | Ca handling mechanisms. Schematic diagram that Release of Ca C from the ER/SR is mediated through IP3 (IP3R) or 2 2 highlights ion channels and transporters directly implicated in Ca C ryanodine (RyR) receptors. The reuptake of Ca C into the ER/SR is 2 2 homeostasis. Influx of Ca C is primarily mediated by VGCC, primarily mediated by sarcoplasmic/ER Ca C ATPase (SERCA). 2 2 2 receptor-mediated Ca C entry, transient receptor potential channels (TRP), Mitochondrial Ca C handling incorporates mitochondrial Ca C uniporter 2 2 2 ligand-gated channels, and store-operated Orai channels that are activated (mCU), Ca C ATPase (mCA) or NaC/Ca C or HC/Ca C exchangers (mNCX, 2 2 by STIM1 protein. Efflux of Ca C is achieved by PM Ca C ATPase mHCX). GP (G proteins); PIP2 (phosphatidylinositol 4,5-bisphosphate); PLC 2 2 (PMCA), NaC/Ca C exchanger (NCX) or NaC/Ca C/KC exchanger (NCKX). (phospholipase C). alternative Ca2C entry mode that is coupled to intracellular Ca2C description of STIM1 as a key component of CRAC was in stores (Gemes et al., 2011). This alternative type of entry, known Drosophila S2 cells in which SOCE is the predominant Ca2C entry as capacitative calcium entry, is triggered upon the depletion of mechanism. Using RNA interference screens of candidate genes, Ca2C stores to facilitate store-operated Ca2C entry (SOCE). The they reported that Stim loss altered SOCE (Roos et al., 2005; latter, SOCE, would in turn replenish the intracellular ER/SR Zhang et al., 2005). It was 1 year after the intracellular STIM1 was stores (Soboloff et al., 2012). Extensive work on this route of discovered that the PM component of CRAC was identified. The calcium influx has established its functional importance in Orai gene, named after the mythological keepers of heaven’s gate, neurons and its ability to supplement cytosolic Ca2C required for was determined as a result of genetic mapping of mutations linked neurotransmission (Berna-Erro et al., 2009; Gemes et al., 2011). to impaired lymphocyte function (Zhang et al., 2006). The SOCE mechanism was then revised to involve the two key players: (1) STORE-OPERATED Ca2+ ENTRY (SOCE): A STILL-DEVELOPING STIM, a transmembrane Ca2C sensor protein that is primarily STORY embedded into the SR/ER membrane; and (2) Orai, an integral About three decades ago, Putney first described the concept of PM protein being the pore-forming subunit of the CRAC channel capacitative Ca2C entry (Putney, 1986). According to this concept, (Figures 1, 2A; Soboloff et al., 2012). the concerted control of both Ca2C influx and Ca2C release Once the key genes governing SOCE were identified, the from intracellular stores orchestrates Ca2C homeostasis. In other interplay between STIM1 and Orai was extensively examined. words, Ca2C influx is modulated by the capacity of the cell to Investigators reported that Orai protein monomers multimerize 2C hold Ca2C. Several studies showed that stimulus-evoked ER/SR to form a Ca channel whose activity is triggered by interaction depletion can trigger subsequent influx of extracellular Ca2C with STIM1 (Penna et al., 2008). Further, STIM-Orai Activating into the cytoplasm as a means to replenish Ca2C in intracellular Region (SOAR) and CRAC Activation Domain (CAD) were iden- stores (Takemura and Putney, 1989; Muallem et al., 1990). These tified as active STIM1 sites necessary to trigger the CRAC current findings led Putney’s model to be revised by indicating that the (Park et al., 2009; Yuan et al., 2009). In addition, high-resolution activation of PM Ca2C channels was a direct consequence of crystal structures of the CAD and the N-terminal region of STIM1 ER/SR depletion (Putney, 1990). Entry of extracellular Ca2C upon as well as the full-length Orai channel were recently characterized store depletion was later suggested to be mediated by Ca2C-release (Stathopulos et al., 2008; Hou et al., 2012; Yang et al., 2012). These activated channels (CRAC) in a process referred to as SOCE (Hoth latter discoveries represent major landmarks towards the eluci- and Penner, 1992; Patterson