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.

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 GRIP1 is required for homeostatic regulation of AMPAR trafficking

2015 ◽  
Vol 112 (32) ◽  
pp. 10026-10031 ◽  
Author(s):  
Han L. Tan ◽  
Bridget N. Queenan ◽  
Richard L. Huganir
Keyword(s):  
Molecular Mechanisms ◽  
Feedback Mechanism ◽  
Homeostatic Plasticity ◽  
Homeostatic Regulation ◽  
Synaptic Scaling ◽  
Negative Feedback Mechanism ◽  
Ampar Trafficking ◽  
The Central Nervous System ◽  
Biochemical Genetic ◽  
Zona Occludens

Homeostatic plasticity is a negative feedback mechanism that stabilizes neurons during periods of perturbed activity. The best-studied form of homeostatic plasticity in the central nervous system is the scaling of excitatory synapses. Postsynaptic AMPA-type glutamate receptors (AMPARs) can be inserted into synapses to compensate for neuronal inactivity or removed to compensate for hyperactivity. However, the molecular mechanisms underlying the homeostatic regulation of AMPARs remain elusive. Here, we show that the expression of GRIP1, a multi-PDZ (postsynaptic density 95/discs large/zona occludens) domain AMPAR-binding protein, is bidirectionally altered by neuronal activity. Furthermore, we observe a subcellular redistribution of GRIP1 and a change in the binding of GRIP1 to GluA2 during synaptic scaling. Using a combination of biochemical, genetic, and electrophysiological methods, we find that loss of GRIP1 blocks the accumulation of surface AMPARs and the scaling up of synaptic strength that occur in response to chronic activity blockade. Collectively, our data point to an essential role of GRIP1-mediated AMPAR trafficking during inactivity-induced synaptic scaling.

scholarly journals Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway

2011 ◽  
Vol 208 (10) ◽  
pp. 1963-1976 ◽  
Author(s):  
Patrick Viatour ◽  
Ursula Ehmer ◽  
Louis A. Saddic ◽  
Craig Dorrell ◽  
Jesper B. Andersen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Liver Tumors ◽  
Expression Profiles ◽  
Notch Pathway ◽  
Gene Expression Profiles ◽  
Feedback Mechanism ◽  
Negative Feedback Mechanism ◽  
Rb Pathway

Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.

Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF

2021 ◽  
Vol 220 (12) ◽  
Author(s):  
Elia Zomot ◽  
Hadas Achildiev Cohen ◽  
Inbal Dagan ◽  
Ruslana Militsin ◽  
Raz Palty
Keyword(s):  
Gene Expression ◽  
Calcium Release ◽  
Cell Receptor ◽  
Crac Channels ◽  
Bidirectional Regulation ◽  
Dependent Inactivation ◽  
Store Operated Calcium Entry ◽  
Crac Channel ◽  
Initial Activation ◽  
Downstream Gene Expression

Store-operated calcium entry (SOCE) through the Ca2+ release–activated Ca2+ (CRAC) channel is a central mechanism by which cells generate Ca2+ signals and mediate Ca2+-dependent gene expression. The molecular basis for CRAC channel regulation by the SOCE-associated regulatory factor (SARAF) remained insufficiently understood. Here we found that following ER Ca2+ depletion, SARAF facilitates a conformational change in the ER Ca2+ sensor STIM1 that relieves an activation constraint enforced by the STIM1 inactivation domain (ID; aa 475–483) and promotes initial activation of STIM1, its translocation to ER–plasma membrane junctions, and coupling to Orai1 channels. Following intracellular Ca2+ rise, cooperation between SARAF and the STIM1 ID controls CRAC channel slow Ca2+-dependent inactivation. We further show that in T lymphocytes, SARAF is required for proper T cell receptor evoked transcription. Taking all these data together, we uncover a dual regulatory role for SARAF during both activation and inactivation of CRAC channels and show that SARAF fine-tunes intracellular Ca2+ responses and downstream gene expression in cells.

Partial unfolding and oligomerization of stromal interaction molecules as an initiation mechanism of store operated calcium entryThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 175-183 ◽  
Author(s):  
Peter B. Stathopulos ◽  
Mitsuhiko Ikura
Keyword(s):  
Peer Review Process ◽  
Cellular Biology ◽  
Published Data ◽  
Initiation Mechanism ◽  
Crac Channels ◽  
Domain Interactions ◽  
Entire Complex ◽  
Crac Channel ◽  
Partial Unfolding ◽  
Selection Of

Spatiotemporally discrete cytoplasmic Ca2+ fluctuations are fundamental eukaryotic signals in myriad physiological and pathophysiological functions. Store-operated Ca2+ entry is the process whereby a decrease in endoplasmic reticulum (ER) luminal Ca2+ levels activates Ca2+ release activated calcium (CRAC) channels on the plasma membrane (PM), providing a sustained Ca2+ elevation to the cytoplasm and ultimately replenishing the ER lumen Ca2+ supply. Stromal interaction molecules (STIMs) are the Ca2+ sensors of the ER lumen, which macromolecularly couple depleted ER Ca2+ to the assembly and opening of PM CRAC channels. The considerable stability difference caused by Ca2+ loading and depletion within the luminal portion of STIMs modulates intramolecular cytoplasmic domain interactions essential to the assembly of PM CRAC channels. Thus, the action of the entire complex is tightly regulated through the Ca2+ sensitivity of luminal STIM domains. Recent structural and biochemical studies suggest that partial unfolding – coupled oligomerization of STIMs is a crucial step in CRAC channel activation. Based on these and other published data, this minireview discusses what is currently known about the molecular mechanism of ER Ca2+ sensing by STIMs.

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.

scholarly journals Regulation of Interorganellar Ca2+ Transfer and NFAT Activation by the Mitochondrial Ca2+ Uniporter

2021 ◽  
Author(s):  
Ryan E. Yoast ◽  
Scott M. Emrich ◽  
Xuexin Zhang ◽  
Ping Xin ◽  
Vikas Arige ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Channel Activity ◽  
Crac Channels ◽  
Store Depletion ◽  
Agonist Stimulation ◽  
Dependent Inactivation ◽  
Nfat Activation ◽  
Crac Channel ◽  
Cellular Bioenergetics ◽  
Trisphosphate Receptor

Mitochondrial Ca2+ uptake is crucial for coupling receptor stimulation to cellular bioenergetics. Further, Ca2+ uptake by respiring mitochondria prevents Ca2+-dependent inactivation (CDI) of store-operated Ca2+ release-activated Ca2+ (CRAC) channels and inhibits Ca2+ extrusion to sustain cytosolic Ca2+ signaling. However, how Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) shapes receptor-evoked interorganellar Ca2+ signaling is unknown. Here, we generated several cell lines with MCU-knockout (MCU-KO) as well as tissue-specific MCU-knockdown mice. We show that mitochondrial depolarization, but not MCU-KO, inhibits store-operated Ca2+ entry (SOCE). Paradoxically, despite enhancing Ca2+ extrusion and promoting CRAC channel CDI, MCU-KO increased cytosolic Ca2+ in response to store depletion. Further, physiological agonist stimulation in MCU-KO cells led to enhanced frequency of cytosolic Ca2+ oscillations, endoplasmic reticulum Ca2+ refilling, NFAT nuclear translocation and proliferation. However, MCU-KO did not affect inositol-1,4,5-trisphosphate receptor activity. Mathematical modeling supports that MCU-KO enhances cytosolic Ca2+, despite limiting CRAC channel activity.

scholarly journals A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Dario Priem ◽  
Michael Devos ◽  
Sarah Druwé ◽  
Arne Martens ◽  
Karolina Slowicka ◽  
...  
Keyword(s):  
Cell Death ◽  
Complex I ◽  
Molecular Mechanisms ◽  
Feedback Mechanism ◽  
Dependent Manner ◽  
Negative Feedback Mechanism ◽  
Signaling Complex ◽  
Induced Apoptosis

Abstract The cytokine TNF promotes inflammation either directly by activating the MAPK and NF-κB signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-κB-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-κB activation. Apart from acting as an NF-κB inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis.

scholarly journals Maternal starvation primes progeny response to nutritional stress

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009932
Author(s):  
Kelly Voo ◽  
Jeralyn Wen Hui Ching ◽  
Joseph Wee Hao Lim ◽  
Seow Neng Chan ◽  
Amanda Yunn Ee Ng ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Environmental Changes ◽  
Nutritional Stress ◽  
Feedback Mechanism ◽  
Starvation Response ◽  
Pathway Activity ◽  
Tor Pathway ◽  
Negative Feedback Mechanism

Organisms adapt to environmental changes in order to survive. Mothers exposed to nutritional stresses can induce an adaptive response in their offspring. However, the molecular mechanisms behind such inheritable links are not clear. Here we report that in Drosophila, starvation of mothers primes the progeny against subsequent nutritional stress. We found that RpL10Ab represses TOR pathway activity by genetically interacting with TOR pathway components TSC2 and Rheb. In addition, starved mothers produce offspring with lower levels of RpL10Ab in the germline, which results in higher TOR pathway activity, conferring greater resistance to starvation-induced oocyte loss. The RpL10Ab locus encodes for the RpL10Ab mRNA and a stable intronic sequence RNA (sisR-8), which collectively repress RpL10Ab pre-mRNA splicing in a negative feedback mechanism. During starvation, an increase in maternally deposited RpL10Ab and sisR-8 transcripts leads to the reduction of RpL10Ab expression in the offspring. Our study suggests that the maternally deposited RpL10Ab and sisR-8 transcripts trigger a negative feedback loop that mediates intergenerational adaptation to nutritional stress as a starvation response.

scholarly journals Comprehensive Mechanism of Gene Silencing and Its Role in Plant Growth and Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Ahmed H. El-Sappah ◽  
Kuan Yan ◽  
Qiulan Huang ◽  
Md. Monirul Islam ◽  
Quanzi Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plant Growth ◽  
Gene Silencing ◽  
Cell Fate ◽  
Crop Production ◽  
Molecular Mechanisms ◽  
Feedback Mechanism ◽  
Transcriptional Gene Silencing ◽  
Coding Region ◽  
Negative Feedback Mechanism

Gene silencing is a negative feedback mechanism that regulates gene expression to define cell fate and also regulates metabolism and gene expression throughout the life of an organism. In plants, gene silencing occurs via transcriptional gene silencing (TGS) and post-transcriptional gene silencing (PTGS). TGS obscures transcription via the methylation of 5′ untranslated region (5′UTR), whereas PTGS causes the methylation of a coding region to result in transcript degradation. In this review, we summarized the history and molecular mechanisms of gene silencing and underlined its specific role in plant growth and crop production.

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