scholarly journals Molecular mechanisms of STIM/Orai communication

2016 ◽  
Vol 310 (8) ◽  
pp. C643-C662 ◽  
Author(s):  
Isabella Derler ◽  
Isaac Jardin ◽  
Christoph Romanin
Keyword(s):  
Molecular Mechanisms ◽  
Signaling Cascades ◽  
Signaling Cascade ◽  
Cellular Processes ◽  
Crac Channels ◽  
Key Players ◽  
Intracellular Ca ◽  
Crac Channel ◽  
Structural Insights ◽  
Molecular Picture

Ca2+entry into the cell via store-operated Ca2+release-activated Ca2+(CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca2+channels open after depletion of intracellular Ca2+stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca2+sensor, while Orai forms a highly Ca2+-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca2+permeation into the cell.

Store-Operated Calcium Channels

2005 ◽  
Vol 85 (2) ◽  
pp. 757-810 ◽  
Author(s):  
Anant B. Parekh ◽  
James W. Putney
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Excitable Cells ◽  
Entry Pathway ◽  
Crac Channels ◽  
Proliferation And Apoptosis ◽  
Intracellular Ca ◽  
Crac Channel ◽  
Cell Growth And Proliferation ◽  
Insight Into

In electrically nonexcitable cells, Ca2+influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major Ca2+entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca2+stores activates Ca2+influx (store-operated Ca2+entry, or capacitative Ca2+entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca2+release-activated Ca2+current, ICRAC. Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for ICRAC-like currents in excitable cells too. In spite of intense research, the signal that relays the store Ca2+content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca2+sensor within the stores, remains elusive. Resolution of these issues would be greatly helped by the identification of the CRAC channel gene. In some systems, evidence suggests that store-operated channels might be related to TRP homologs, although no consensus has yet been reached. Better understood are mechanisms that inactivate store-operated entry and hence control the overall duration of Ca2+entry. Recent work has revealed a central role for mitochondria in the regulation of ICRAC, and this is particularly prominent under physiological conditions. ICRACtherefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of ICRACand other store-operated Ca2+currents and how they are regulated, and we consider recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca2+entry pathway.

scholarly journals Regulation of Store-Operated Ca2+ Entry by SARAF

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1887
Author(s):  
Inbal Dagan ◽  
Raz Palty
Keyword(s):  
Molecular Mechanisms ◽  
Feedback Mechanism ◽  
Cellular Biology ◽  
Excitable Cells ◽  
Major Pathway ◽  
Negative Feedback Mechanism ◽  
Crac Channels ◽  
Dependent Inactivation ◽  
Crac Channel ◽  
The One

Calcium (Ca2+) signaling plays a dichotomous role in cellular biology, controlling cell survival and proliferation on the one hand and cellular toxicity and cell death on the other. Store-operated Ca2+ entry (SOCE) by CRAC channels represents a major pathway for Ca2+ entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) and the plasma-membrane Ca2+ channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca2+ flux is regulated by a negative feedback mechanism of slow Ca2+ dependent inactivation (SCDI). The identification of the SOCE-associated regulatory factor (SARAF) and investigations of its role in SCDI have led to new functional and molecular insights into how SOCE is controlled. In this review, we provide an overview of the functional and molecular mechanisms underlying SCDI and discuss how the interaction between SARAF, STIM1, and Orai1 shapes Ca2+ signaling in cells.

scholarly journals Clinical Importance of Wnt5a in the Pathogenesis of Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Mehran Pashirzad ◽  
Thozhukat Sathyapalan ◽  
Amirhossein Sahebkar
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Clinical Importance ◽  
Signaling Cascades ◽  
Cancer Type ◽  
Invasion And Metastasis ◽  
Cellular Processes ◽  
Wnt5a Expression ◽  
Noncanonical Signaling

Wnt5a is one of the potent signaling molecules that initiates responses involved in cancer through activation of both canonical and noncanonical signaling cascades. Wnt5a both directly and indirectly triggers cancer-associated signaling pathways based on the cancer type. In colorectal cancer (CRC), altering Wnt5a expression can influence several cellular processes of tumor cells, including proliferation, differentiation, migration, invasion, and metastasis. This review summarizes the molecular mechanisms and clinical importance of Wnt5a in the pathogenesis of CRC for better understanding the pathogenesis and its potential role as a prognostic marker and as an appropriate therapeutic target in the treatment of this disease in the future.

scholarly journals Changing calcium: CRAC channel (STIM and Orai) expression, splicing, and posttranslational modifiers

2016 ◽  
Vol 310 (9) ◽  
pp. C701-C709 ◽  
Author(s):  
Barbara A. Niemeyer
Keyword(s):  
Immune Cells ◽  
Posttranslational Modifications ◽  
Splice Variants ◽  
Effector Functions ◽  
Crac Channels ◽  
Intracellular Ca ◽  
Crac Channel ◽  
The Individual ◽  
Sensor Proteins ◽  
Temporal Spread

A wide variety of cellular function depends on the dynamics of intracellular Ca2+ signals. Especially for relatively slow and lasting processes such as gene expression, cell proliferation, and often migration, cells rely on the store-operated Ca2+ entry (SOCE) pathway, which is particularly prominent in immune cells. SOCE is initiated by the sensor proteins (STIM1, STIM2) located within the endoplasmic reticulum (ER) registering the Ca2+ concentration within the ER, and upon its depletion, cluster and trap Orai (Orai1-3) proteins located in the plasma membrane (PM) into ER-PM junctions. These regions become sites of highly selective Ca2+ entry predominantly through Orai1-assembled channels, which, among other effector functions, is necessary for triggering NFAT translocation into the nucleus. What is less clear is how the spatial and temporal spread of intracellular Ca2+ is shaped and regulated by differential expression of the individual SOCE genes and their splice variants, their heteromeric combinations and pre- and posttranslational modifications. This review focuses on principle mechanisms regulating expression, splicing, and targeting of Ca2+ release-activated Ca2+ (CRAC) channels.

Enhanced exocytotic-like insertion of Orai1 into the plasma membrane upon intracellular Ca2+ store depletion

2008 ◽  
Vol 294 (6) ◽  
pp. C1323-C1331 ◽  
Author(s):  
Geoffrey E. Woodard ◽  
Ginés M. Salido ◽  
Juan A. Rosado
Keyword(s):  
Plasma Membrane ◽  
Botulinum Neurotoxin ◽  
Surface Expression ◽  
Membrane Expression ◽  
Botulinum Neurotoxin A ◽  
Crac Channels ◽  
Store Depletion ◽  
Protein Receptor ◽  
Intracellular Ca ◽  
Crac Channel

Ca+ release-activated Ca2+ (CRAC) channels are activated when free Ca2+ concentration in the intracellular stores is substantially reduced and mediate sustained Ca2+ entry. Recent studies have identified Orai1 as a CRAC channel subunit. Here we demonstrate that passive Ca2+ store depletion using the inhibitor of the sarcoendoplasmic reticulum Ca2+-ATPase, thapsigargin (TG), enhances the surface expression of Orai1, a process that depends on rises in cytosolic free Ca2+ concentration, as demonstrated in cells loaded with dimethyl BAPTA, an intracellular Ca2+ chelator that prevented TG-evoked cytosolic free Ca2+ concentration elevation. Similar results were observed with a low concentration of carbachol. Cleavage of the soluble N-ethylmaleimide-sensitive-factor attachment protein receptor, synaptosomal-assiciated protein-25 (SNAP-25), with botulinum neurotoxin A impaired TG-induced increase in the surface expression of Orai1. In addition, SNAP-25 cleaving by botulinum neurotoxin A reduces the maintenance but not the initial stages of store-operated Ca2+ entry. In aggregate, these findings demonstrate that store depletion enhances Orai1 plasma membrane expression in an exocytotic manner that involves SNAP-25, a process that contributes to store-dependent Ca2+ entry.

Abstract 14278: Microglial Calcium Activity During Ischemic Stroke

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kathryn N Kearns ◽  
Lei Liu ◽  
Khadijeh A Sharifi ◽  
Kenneth A Stauderman ◽  
Min S Park ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Calcium Release ◽  
Therapeutic Benefit ◽  
Artery Occlusion ◽  
Two Photon Microscopy ◽  
Crac Channels ◽  
Intracellular Ca ◽  
Crac Channel ◽  
Cerebral Artery Occlusion

Introduction: Ischemic stroke triggers waves of propagating action potentials followed by a loss of homeostatic ion gradients, known as cortical spreading depolarizations (SD). Our data indicate that microglia respond to SD by raising intracellular Ca 2+ , triggering a release of proinflammatory cytokines that may exacerbate post-stroke morbidity. Hypothesis: Inhibiting calcium release-activated calcium (CRAC) channels may block microglial Ca2+ influx and activation to potentially provide therapeutic benefit in ischemic stroke. Methods: We generated a mouse line expressing the Ca2+ indicator GCaMP5 in cortical microglia. Using two-photon microscopy, we imaged microglia in vivo following physical stroke via middle cerebral artery occlusion (MCAo) or chemical stroke via 1M KCl solution application. Controls were compared to mice treated with lipopolysaccharide (LPS) to mimic the inflammation of ischemic stroke. To study CRAC channels as a therapeutic target, we administered CM-EX-137, a CRAC channel blocker, and compared Ca2+ activity to controls. Results: We identified periodical Ca2+ waves in cortical microglia following MCAo (Fig. 1A), or localized KCl application (Fig. 1B-E). Further, when compared to controls, LPS-exposed mice expressed significantly greater microglial Ca2+ activity during KCl-triggered SD (Fig. 1C). Additionally, administration of CM-EX-137 effectively abolished the Ca2+ signals in the microglia and propagation of SD upon application of KCl (Fig. 1E). Conclusions: Blocking the Ca2+ influx into microglia after ischemic stroke may decrease the frequency of SD and reduce microglial activation, potentially leading to smaller stroke volumes and improved clinical outcomes. Figure 1: Microglial Ca 2+ after SD. (A) Ca 2+ transients in microglia after MCAo. (B) KCl-induced Ca 2+ activity in naïve microglia. (C) KCl-induced Ca 2+ activity after LPS. (D, E) KCl-induced Ca 2+ wave after (D) vehicle or (E) CM-EX-137 administration.

scholarly journals STIM1, an essential and conserved component of store-operated Ca2+ channel function

2005 ◽  
Vol 169 (3) ◽  
pp. 435-445 ◽  
Author(s):  
Jack Roos ◽  
Paul J. DiGregorio ◽  
Andriy V. Yeromin ◽  
Kari Ohlsen ◽  
Maria Lioudyno ◽  
...  
Keyword(s):  
T Cells ◽  
Mammalian Cells ◽  
Hek293 Cells ◽  
Complete Suppression ◽  
Patch Clamp Recording ◽  
Common Component ◽  
Cellular Processes ◽  
Crac Channels ◽  
Crac Channel ◽  
Molecular Components

Store-operated Ca2+ (SOC) channels regulate many cellular processes, but the underlying molecular components are not well defined. Using an RNA interference (RNAi)-based screen to identify genes that alter thapsigargin (TG)-dependent Ca2+ entry, we discovered a required and conserved role of Stim in SOC influx. RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca2+ entry. Patch-clamp recording revealed nearly complete suppression of the Drosophila Ca2+ release-activated Ca2+ (CRAC) current that has biophysical characteristics similar to CRAC current in human T cells. Similarly, knockdown of the human homologue STIM1 significantly reduced CRAC channel activity in Jurkat T cells. RNAi-mediated knockdown of STIM1 inhibited TG- or agonist-dependent Ca2+ entry in HEK293 or SH-SY5Y cells. Conversely, overexpression of STIM1 in HEK293 cells modestly enhanced TG-induced Ca2+ entry. We propose that STIM1, a ubiquitously expressed protein that is conserved from Drosophila to mammalian cells, plays an essential role in SOC influx and may be a common component of SOC and CRAC channels.

Ca2+ release-activated Ca2+ channels are responsible for histamine-induced Ca2+ entry, permeability increase, and interleukin synthesis in lymphatic endothelial cells

2020 ◽  
Vol 318 (5) ◽  
pp. H1283-H1295 ◽  
Author(s):  
Hongjiang Si ◽  
Jian Wang ◽  
Cynthia J. Meininger ◽  
Xu Peng ◽  
David C. Zawieja ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Endothelial Barrier ◽  
Channel Blockers ◽  
Lymphatic Endothelial Cells ◽  
Histamine Stimulation ◽  
Cellular Effects ◽  
Crac Channels ◽  
Crac Channel

The lymphatic functions in maintaining lymph transport, and immune surveillance can be impaired by infections and inflammation, thereby causing debilitating disorders, such as lymphedema and inflammatory bowel disease. Histamine is a key inflammatory mediator known to trigger vasodilation and vessel hyperpermeability upon binding to its receptors and evoking intracellular Ca2+ ([Ca2+]i) dynamics for downstream signal transductions. However, the exact molecular mechanisms beneath the [Ca2+]i dynamics and the downstream cellular effects have not been elucidated in the lymphatic system. Here, we show that Ca2+ release-activated Ca2+ (CRAC) channels, formed by Orai1 and stromal interaction molecule 1 (STIM1) proteins, are required for the histamine-elicited Ca2+ signaling in human dermal lymphatic endothelial cells (HDLECs). Blockers or antagonists against CRAC channels, phospholipase C, and H1R receptors can all significantly diminish the histamine-evoked [Ca2+]i dynamics in lymphatic endothelial cells (LECs), while short interfering RNA-mediated knockdown of endogenous Orai1 or STIM1 also abolished the Ca2+ entry upon histamine stimulation in LECs. Furthermore, we find that histamine compromises the lymphatic endothelial barrier function by increasing the intercellular permeability and disrupting vascular endothelial-cadherin integrity, which is remarkably attenuated by CRAC channel blockers. Additionally, the upregulated expression of inflammatory cytokines, IL-6 and IL-8, after histamine stimulation was abolished by silencing Orai1 or STIM1 with RNAi in LECs. Taken together, our data demonstrated the essential role of CRAC channels in mediating the [Ca2+]i signaling and downstream endothelial barrier and inflammatory functions induced by histamine in the LECs, suggesting a promising potential to relieve histamine-triggered vascular leakage and inflammatory disorders in the lymphatics by targeting CRAC channel functions.

scholarly journals Role of Long Non-Coding RNA Polymorphisms in Cancer Chemotherapeutic Response

2021 ◽  
Vol 11 (6) ◽  
pp. 513
Author(s):  
Zheng Zhang ◽  
Meng Gu ◽  
Zhongze Gu ◽  
Yan-Ru Lou
Keyword(s):  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Cellular Processes ◽  
Dna And Rna ◽  
Chemotherapeutic Response ◽  
Non Coding Rna ◽  
Response To Chemotherapy ◽  
Personalized Oncology ◽  
Long Non Coding Rna

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length of more than 200 nucleotides, their biological roles have been increasingly revealed in recent years. They regulate many cellular processes, from pluripotency to cancer. Interestingly, abnormal expression or dysfunction of lncRNAs is closely related to the occurrence of human diseases, including cancer and degenerative neurological diseases. Particularly, their polymorphisms have been found to be associated with altered drug response and/or drug toxicity in cancer treatment. However, molecular mechanisms are not yet fully elucidated, which are expected to be discovered by detailed studies of RNA–protein, RNA–DNA, and RNA–lipid interactions. In conclusion, lncRNAs polymorphisms may become biomarkers for predicting the response to chemotherapy in cancer patients. Here we review and discuss how gene polymorphisms of lncRNAs affect cancer chemotherapeutic response. This knowledge may pave the way to personalized oncology treatments.

scholarly journals DEAD-box helicases modulate dicing body formation in Arabidopsis

2021 ◽  
Vol 7 (18) ◽  
pp. eabc6266
Author(s):  
Qi Li ◽  
Ningkun Liu ◽  
Qing Liu ◽  
Xingguo Zheng ◽  
Lu Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Turnip Mosaic Virus ◽  
Liquid Droplets ◽  
Phase Separations ◽  
Body Formation ◽  
Cellular Processes ◽  
Dead Box ◽  
Body Components ◽  
Liquid Phase Separations ◽  
Spatiotemporal Control

Eukaryotic cells contain numerous membraneless organelles that are made from liquid droplets of proteins and nucleic acids and that provide spatiotemporal control of various cellular processes. However, the molecular mechanisms underlying the formation and rapid stress-induced alterations of these organelles are relatively uncharacterized. Here, we investigated the roles of DEAD-box helicases in the formation and alteration of membraneless nuclear dicing bodies (D-bodies) in Arabidopsis thaliana. We uncovered that RNA helicase 6 (RH6), RH8, and RH12 are previously unidentified D-body components. These helicases interact with and promote the phase separation of SERRATE, a key component of D-bodies, and drive the formation of D-bodies through liquid-liquid phase separations (LLPSs). The accumulation of these helicases in the nuclei decreases upon Turnip mosaic virus infections, which couples with the decrease of D-bodies. Our results thus reveal the key roles of RH6, RH8, and RH12 in modulating D-body formation via LLPSs.

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