Regulation of Ca2+ release-activated Ca2+channels by INAD and Ca2+ influx factor

2003 ◽  
Vol 284 (2) ◽  
pp. C497-C505 ◽  
Author(s):  
Zhengchang Su ◽  
Douglas S. Barker ◽  
Peter Csutora ◽  
Theresa Chang ◽  
Richard L. Shoemaker ◽  
...  
Keyword(s):  
Cell Types ◽  
Model System ◽  
Low Molecular Weight ◽  
Coupling Mechanism ◽  
Crac Channels ◽  
Store Depletion ◽  
Drosophila Protein ◽  
Mammalian Homologue ◽  
Trisphosphate Receptor ◽  
Ca2 Channels

The coupling mechanism between depletion of Ca2+ stores in the endoplasmic reticulum and plasma membrane store-operated ion channels is fundamental to Ca2+ signaling in many cell types and has yet to be completely elucidated. Using Ca2+release-activated Ca2+ (CRAC) channels in RBL-2H3 cells as a model system, we have shown that CRAC channels are maintained in the closed state by an inhibitory factor rather than being opened by the inositol 1,4,5-trisphosphate receptor. This inhibitory role can be fulfilled by the Drosophila protein INAD (inactivation-no after potential D). The action of INAD requires Ca2+ and can be reversed by a diffusible Ca2+ influx factor. Thus the coupling between the depletion of Ca2+ stores and the activation of CRAC channels may involve a mammalian homologue of INAD and a low-molecular-weight, diffusible store-depletion signal.

Calcium entry and the control of calcium oscillations

2003 ◽  
Vol 31 (5) ◽  
pp. 916-919 ◽  
Author(s):  
T.J. Shuttleworth ◽  
O. Mignen
Keyword(s):  
Arachidonic Acid ◽  
Critical Role ◽  
Cell Types ◽  
Calcium Entry ◽  
Calcium Oscillations ◽  
Reciprocal Regulation ◽  
Crac Channels ◽  
Store Depletion ◽  
Low Concentrations ◽  
Ca2 Channels

During oscillatory Ca2+ signals, the agonist-induced enhanced entry of extracellular Ca2+ plays a critical role in modulating the frequency of the oscillations. Although it was originally assumed that the entry of Ca2+ under these conditions occurred via the well-known, and apparently ubiquitous, store-operated mechanism, subsequent studies suggested that this was unlikely. It is now known that, in many cell types, a novel non-capacitative Ca2+-selective pathway whose activation is dependent on arachidonic acid is responsible, and the channels involved [ARC channels (arachidonate-regulated Ca2+ channels)] have been characterized. These ARC channels co-exist with the store-operated CRAC channels (Ca2+-release-activated Ca2+ channel) in cells, but each plays a unique and non-overlapping role in Ca2+ signalling. In particular, it is the ARC channels that are specifically activated at the low agonist concentrations that give rise to oscillatory Ca2+ signals and provide the predominant mode of Ca2+ entry under these conditions. The indications are that Ca2+ entry through the ARC channels increases the likelihood that low concentrations of Ins(1,4,5)P3 will trigger repetitive Ca2+ release. At higher agonist concentrations, store-depletion is more complete and sustained resulting in the activation of CRAC channels. At the same time the ARC channels are turned off, resulting in what we have described as a reciprocal regulation of these two distinct Ca2+ entry pathways.

Mechanisms of capacitative calcium entry

2001 ◽  
Vol 114 (12) ◽  
pp. 2223-2229 ◽  
Author(s):  
James W. Putney ◽  
Lisa M. Broad ◽  
Franz-Josef Braun ◽  
Jean-Philippe Lievremont ◽  
Gary St J. Bird
Keyword(s):  
Plasma Membrane ◽  
Phospholipase C ◽  
Binding Sites ◽  
Cell Types ◽  
Store Depletion ◽  
Blocking Effects ◽  
Conformational Coupling ◽  
Phosphatidylinositol 4 ◽  
Filling State ◽  
Ca2 Channels

Capacitative Ca2+ entry involves the regulation of plasma membrane Ca2+ channels by the filling state of intracellular Ca2+ stores in the endoplasmic reticulum (ER). Several theories have been advanced regarding the mechanism by which the stores communicate with the plasma membrane. One such mechanism, supported by recent findings, is conformational coupling: inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) receptors in the ER may sense the fall in Ca2+ levels through Ca2+-binding sites on their lumenal domains, and convey this conformational information directly by physically interacting with Ca2+ channels in the plasma membrane. In support of this idea, in some cell types, store-operated channels in excised membrane patches appear to depend on the presence of both Ins(1,4,5)P3 and Ins(1,4,5)P3 receptors for activity; in addition, inhibitors of Ins(1,4,5)P3 production that either block phospholipase C or inhibit phosphatidylinositol 4-kinase can block capacitative Ca2+ entry. However, the electrophysiological current underlying capacitative Ca2+ entry is not blocked by an Ins(1,4,5)P3 receptor antagonist, and the blocking effects of a phospholipase C inhibitor are not reversed by the intracellular application of Ins(1,4,5)P3. Furthermore, cells whose Ins(1,4,5)P3 receptor genes have been disrupted can nevertheless maintain their capability to activate capacitative Ca2+ entry channels in response to store depletion. A tentative conclusion is that multiple mechanisms for signaling capacitative Ca2+ entry may exist, and involve conformational coupling in some cell types and perhaps a diffusible signal in others.

scholarly journals STIM1L is a new actin-binding splice variant involved in fast repetitive Ca2+ release

2011 ◽  
Vol 194 (2) ◽  
pp. 335-346 ◽  
Author(s):  
Basile Darbellay ◽  
Serge Arnaudeau ◽  
Charles R. Bader ◽  
Stephane Konig ◽  
Laurent Bernheim
Keyword(s):  
Plasma Membrane ◽  
Intracellular Signaling ◽  
Cell Types ◽  
Actin Binding ◽  
Slow Process ◽  
Excitable Cells ◽  
Store Depletion ◽  
Mammalian Tissues ◽  
New Protein ◽  
Ca2 Channels

Cytosolic Ca2+ signals encoded by repetitive Ca2+ releases rely on two processes to refill Ca2+ stores: Ca2+ reuptake from the cytosol and activation of a Ca2+ influx via store-operated Ca2+ entry (SOCE). However, SOCE activation is a slow process. It is delayed by >30 s after store depletion because stromal interaction molecule 1 (STIM1), the Ca2+ sensor of the intracellular stores, must form clusters and migrate to the membrane before being able to open Orai1, the plasma membrane Ca2+ channel. In this paper, we identify a new protein, STIM1L, that colocalizes with Orai1 Ca2+ channels and interacts with actin to form permanent clusters. This property allowed the immediate activation of SOCE, a characteristic required for generating repetitive Ca2+ signals with frequencies within seconds such as those frequently observed in excitable cells. STIM1L was expressed in several mammalian tissues, suggesting that many cell types rely on this Ca2+ sensor for their Ca2+ homeostasis and intracellular signaling.

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 S-acylation of Orai1 regulates store-operated Ca2+ entry

2021 ◽  
Vol 135 (5) ◽  
Author(s):  
Savannah J. West ◽  
Goutham Kodakandla ◽  
Qioachu Wang ◽  
Ritika Tewari ◽  
Michael X. Zhu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Cell Types ◽  
Central Component ◽  
Channel Activation ◽  
Crac Channels ◽  
Store Depletion ◽  
Crac Channel ◽  
Underlying Mechanisms ◽  
Different Cell Types

ABSTRACT Store-operated Ca2+ entry is a central component of intracellular Ca2+ signaling pathways. The Ca2+ release-activated channel (CRAC) mediates store-operated Ca2+ entry in many different cell types. The CRAC channel is composed of the plasma membrane (PM)-localized Orai1 channel and endoplasmic reticulum (ER)-localized STIM1 Ca2+ sensor. Upon ER Ca2+ store depletion, Orai1 and STIM1 form complexes at ER–PM junctions, leading to the formation of activated CRAC channels. Although the importance of CRAC channels is well described, the underlying mechanisms that regulate the recruitment of Orai1 to ER–PM junctions are not fully understood. Here, we describe the rapid and transient S-acylation of Orai1. Using biochemical approaches, we show that Orai1 is rapidly S-acylated at cysteine 143 upon ER Ca2+ store depletion. Importantly, S-acylation of cysteine 143 is required for Orai1-mediated Ca2+ entry and recruitment to STIM1 puncta. We conclude that store depletion-induced S-acylation of Orai1 is necessary for recruitment to ER–PM junctions, subsequent binding to STIM1 and channel activation.

scholarly journals Thapsigargin inhibits voltage-activated calcium channels in adrenal glomerulosa cells

1993 ◽  
Vol 296 (2) ◽  
pp. 309-312 ◽  
Author(s):  
M F Rossier ◽  
C P Python ◽  
M M Burnay ◽  
W Schlegel ◽  
M B Vallotton ◽  
...  
Keyword(s):  
Cell Types ◽  
Inhibitory Effect ◽  
Zona Glomerulosa ◽  
High Threshold ◽  
Patch Clamp Technique ◽  
Dual Effect ◽  
Blocking Voltage ◽  
Current Voltage ◽  
Glomerulosa Cells ◽  
Ca2 Channels

Thapsigargin, an inhibitor of the microsomal Ca2+ pumps, has been extensively used to study the intracellular Ca2+ pool participating in the generation of the agonist-induced Ca2+ signal in various cell types. A dual effect of this agent was observed in bovine adrenal zona glomerulosa cells. At nanomolar concentrations, thapsigargin stimulated a sustained Ca2+ influx, probably resulting from Ca(2+)-store depletion. In contrast, when added at micromolar concentrations, thapsigargin prevented the rise in cytosolic free Ca2+ concentration ([Ca2+]c) induced by K+. This inhibitory effect of thapsigargin on voltage-activated Ca2+ channels was confirmed by measuring Ba2+ currents by the patch-clamp technique. Both low-threshold (T-type) and high-threshold (L-type) Ca2+ channels were affected by micromolar concentrations of thapsigargin. Analysis of the current-voltage relationship for T-type channels revealed that thapsigargin did not modify the sensitivity of these channels to the voltage, but decreased the maximal current flowing through the channels. In conclusion, thapsigargin appears to exert a dual effect on adrenal glomerulosa cells. At lower concentrations, this agent induces a sustained Ca2+ entry, whereas at higher concentrations it decreases [Ca2+]c by blocking voltage-activated Ca2+ channels.

A ligand-receptor model for the cohesive behaviour of Dictyostelium discoideum axenic cells

1979 ◽  
Vol 37 (1) ◽  
pp. 157-167
Author(s):  
A.R. Jaffe ◽  
A.P. Swan ◽  
D.R. Garrod
Keyword(s):  
Molecular Weight ◽  
Stationary Phase ◽  
Chelating Agent ◽  
Cell Types ◽  
Low Molecular Weight ◽  
Receptor Model ◽  
Phase Growth ◽  
Developmentally Regulated ◽  
Receptor System ◽  
Contact Sites

Axenically grown cells of D. discoideum Ax-2 harvested in the log phase of growth, cohere rapidly when shaken in phosphate buffer. After 3.5 days in the stationary phase of growth, cells become completely non-cohesive. Although they do not stick to each other, stationary phase cells do stick to both log phase cells and aggregation-competent cells. The cohesion of stationary phase cells with these other 2 cell types is inhibited by both EDTA and the low-molecular-weight factor which we have previously demonstrated in stationary-phase growth medium. There is a decline in the sensitivity of slime mould cell cohesion to the low-molecular-weight inhibitory factor as the cells become aggregation-competent. This effect parallels the developmentally-regulated decline in sensitivity to EDTA. The low-molecular-weight inhibitor is not a chelating agent, however. The effect of the inhibitor seems to be specifically against contact sites-B mediated cohesion. We suggest that the simplest cohesive mechanism which can explain our results, is that the EDTA-sensitive cohesion of log phase cells could be dependent on a ligand-receptor system.

scholarly journals Dynactin is required for bidirectional organelle transport

2003 ◽  
Vol 160 (3) ◽  
pp. 297-301 ◽  
Author(s):  
Sean W. Deacon ◽  
Anna S. Serpinskaya ◽  
Patricia S. Vaughan ◽  
Monica Lopez Fanarraga ◽  
Isabelle Vernos ◽  
...  
Keyword(s):  
Cell Types ◽  
Cytoplasmic Dynein ◽  
Opposite Polarity ◽  
Model System ◽  
Organelle Transport ◽  
Transport Activity ◽  
Microtubule Motors ◽  
Microtubule Motor ◽  
Dynactin Complex ◽  
Binding Subunit

Kinesin II is a heterotrimeric plus end–directed microtubule motor responsible for the anterograde movement of organelles in various cell types. Despite substantial literature concerning the types of organelles that kinesin II transports, the question of how this motor associates with cargo organelles remains unanswered. To address this question, we have used Xenopus laevis melanophores as a model system. Through analysis of kinesin II–mediated melanosome motility, we have determined that the dynactin complex, known as an anchor for cytoplasmic dynein, also links kinesin II to organelles. Biochemical data demonstrates that the putative cargo-binding subunit of Xenopus kinesin II, Xenopus kinesin II–associated protein (XKAP), binds directly to the p150Glued subunit of dynactin. This interaction occurs through aa 530–793 of XKAP and aa 600–811 of p150Glued. These results reveal that dynactin is required for transport activity of microtubule motors of opposite polarity, cytoplasmic dynein and kinesin II, and may provide a new mechanism to coordinate their activities.

scholarly journals Characterisation of GLUT4 trafficking in HeLa cells: comparable kinetics and orthologous trafficking mechanisms to 3T3-L1 adipocytes

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8751 ◽  
Author(s):  
Silke Morris ◽  
Niall D. Geoghegan ◽  
Jessica B.A. Sadler ◽  
Anna M. Koester ◽  
Hannah L. Black ◽  
...  
Keyword(s):  
Cell Surface ◽  
Hela Cells ◽  
Glucose Transporter ◽  
Characteristic Property ◽  
Cell Types ◽  
Model System ◽  
Human Model ◽  
Small Scale ◽  
Glucose Transporter Glut4 ◽  
Surface Fusion

Insulin-stimulated glucose transport is a characteristic property of adipocytes and muscle cells and involves the regulated delivery of glucose transporter (GLUT4)-containing vesicles from intracellular stores to the cell surface. Fusion of these vesicles results in increased numbers of GLUT4 molecules at the cell surface. In an attempt to overcome some of the limitations associated with both primary and cultured adipocytes, we expressed an epitope- and GFP-tagged version of GLUT4 (HA–GLUT4–GFP) in HeLa cells. Here we report the characterisation of this system compared to 3T3-L1 adipocytes. We show that insulin promotes translocation of HA–GLUT4–GFP to the surface of both cell types with similar kinetics using orthologous trafficking machinery. While the magnitude of the insulin-stimulated translocation of GLUT4 is smaller than mouse 3T3-L1 adipocytes, HeLa cells offer a useful, experimentally tractable, human model system. Here, we exemplify their utility through a small-scale siRNA screen to identify GOSR1 and YKT6 as potential novel regulators of GLUT4 trafficking in human cells.

scholarly journals Evidence that Ca2+-release-activated Ca2+ channels in rat hepatocytes are required for the maintenance of hormone-induced Ca2+ oscillations

2003 ◽  
Vol 370 (2) ◽  
pp. 695-702 ◽  
Author(s):  
Roland B. GREGORY ◽  
Gregory J. BARRITT
Keyword(s):  
High Selectivity ◽  
Rat Hepatocytes ◽  
Isolated Hepatocytes ◽  
Cation Channels ◽  
Isolated Rat Hepatocytes ◽  
Pharmacological Agents ◽  
Crac Channels ◽  
Kinetics Of ◽  
Ca2 Channels

Store-operated Ca2+ channels in liver cells have been shown previously to exhibit a high selectivity for Ca2+ and to have properties indistinguishable from those of Ca2+-release-activated Ca2+ (CRAC) channels in mast cells and lymphocytes [Rychkov, Brereton, Harland and Barritt (2001) Hepatology 33, 938—947]. The role of CRAC channels in the maintenance of hormone-induced oscillations in the cytoplasmic free Ca2+ concentration ([Ca2+]cyt) in isolated rat hepatocytes was investigated using several inhibitors of CRAC channels. 2-Aminoethyl diphenylborate (2-APB; 75μM), Gd3+ (1μM) and 1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride (SK&F 96365; 50μM) each inhibited vasopressin- and adrenaline (epinephrine)-induced Ca2+ oscillations (measured using fura-2). The characteristics of this inhibition were similar to those of inhibition caused by decreasing the extracellular Ca2+ concentration to zero by addition of EGTA. The effect of 2-APB was reversible. In contrast, LOE-908 {(R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamidemesylate}(30μM), used commonly to block Ca2+ inflow through intracellular-messenger-activated, non-selective cation channels, did not inhibit the Ca2+ oscillations. In the absence of added extracellular Ca2+, 2-APB, Gd3+ and SK&F 96365 did not alter the kinetics of the increase in [Ca2+]cyt induced by a concentration of adrenaline or vasopressin that induces continuous Ca2+ oscillations at the physiological extracellular Ca2+ concentration. Ca2+ inflow through non-selective cation channels activated by maitotoxin could not restore Ca2+ oscillations in cells treated with 2-APB to block Ca2+ inflow through CRAC channels. Evidence for the specificity of the pharmacological agents for inhibition of CRAC channels under the conditions of the present experiments with hepatocytes is discussed. It is concluded that Ca2+ inflow through CRAC channels is required for the maintenance of hormone-induced Ca2+ oscillations in isolated hepatocytes.

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