Endoplasmic reticulumInhibitorSOCESERCAIntracellular calcium storesMobilizationReceptorsPumpStimulationInositolNeuronsApoptosisExtracellularAntibodyInhibitsCellsConcentrationSuppressionInfluxRyanodine-sensitiveIncreasing cytosolicUnfolded proteinConcentrationsEntryChannelsAgentActivityActivationCellFormationTreatment
Endoplasmic reticulum10
- Thapsigargin is a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). (wikipedia.org)
- SERCA is responsible for pumping cytosolic Ca 2+ into the endoplasmic reticulum (ER) store and thus maintaining the intracellular concentrations of Ca 2+ both in the cytosol and in the ER store. (jneurosci.org)
- We showed that passive endoplasmic reticulum (ER) depletion by thapsigargin or cell stimulation by histamine activated a similar Ca(2+)-release-activated Ca(2+) current (CRAC)-like current when 10 mM Ba(2+)/2 mM Ca(2+) was present in the extracellular solution. (unige.ch)
- Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. (kcl.ac.uk)
- 2. Thapsigargin, a specific inhibitor of Ca 2+ -ATPase on the endoplasmic reticulum, and ryanodine and ruthenium red, inhibitors of the ryanodine receptor, blocked the induction of LTD. 3. (elsevierpure.com)
- 50 nM) it inhibits Ca 2+ accumulation by endoplasmic reticulum pools, whereas at higher concentrations (200-2000 nM) thapsigargin blocks high-voltage-activated Ca 2+ currents, reducing Ca 2+ entry into the cell. (uaeu.ac.ae)
- In intact arterial segments pre-stimulated with 20 mM K(+), 5-HT-evoked contractions were unaffected by 1 microM thapsigargin, which inhibits sarco- and endoplasmic reticulum calcium-ATPases. (ox.ac.uk)
- One popular model for the activation of store-operated Ca2+ influx is the secretion-like coupling mechanism, in which peripheral endoplasmic reticulum moves to the plasma membrane upon store depletion thereby enabling inositol 1,4,5-trisphosphate (InsP3) receptors on the stores to bind to, and thus activate, store-operated Ca2+ channels. (ox.ac.uk)
- The NO-induced Ca2+ response primarily involves mobilization of endoplasmic reticulum Ca2+ stores, since the response was retained when cells were transferred to low Ca2+ medium, and completely inhibited when cells were pretreated with 10 microM thapsigargin. (ox.ac.uk)
- The values of endoplasmic reticulum Ca 2+ -pool and store-operated Ca 2+ entry (SOCE) were estimated in rat thymocytes and Jurkat cells loaded with indo-1 and treated with thapsigargin. (ukrbiochemjournal.org)
Inhibitor6
- Activity Thapsigargin is an extremely tight-binding inhibitor of intracellular Ca 2+ pumps, but initially described as a tumor promoting agent which induces rapid Ca 2+ release from intracellular stores 1 . (alomone.com)
- Thapsigargin , derived from the plant genus Thapsia 1,2 , is an extremely tight-binding inhibitor of intracellular Ca 2+ pumps. (alomone.com)
- Results Stim1 raises SOCE and apoptosis in IDH1 Inhibitor 2 DT40 B cells Recent work offers described an important part for Stim1 in store-operated Ca2+ access (SOCE)13C15. (mdm-inhibitors.com)
- Chelation of extracellular Ca2+ by EGTA efficiently abrogated the thapsigargin- or CPA-induced pErk response, demonstrating the strong Erk activation observed in the Stim1-overexpressing DT40 cells is due to the increased IDH1 Inhibitor 2 SOCE in these cells. (mdm-inhibitors.com)
- the ER stress-inducing agent thapsigargin an inhibitor from the sarco(endo)plasmic reticulum Ca2+ pump that triggers Ca2+ efflux from ER shops elevated cytosolic [Ca2+] and induced TF PCA. (healthcarecoremeasures.com)
- 2-Aminoethoxydiphenyl borate (APB), a blocker of store-operated calcium channels (SOCs), and bisindolylmaleimide I (Bis I), a broad-spectrum protein kinase C (PKC) inhibitor, inhibited the basal and synergic effects of IL-6 secretion in response to calcium-mobilizing agents and TNF-α, but did not prevent the abrogated effect of RANTES secretion. (tmu.edu.tw)
SOCE8
- Exercise promotes the formation of intracellular junctions in skeletal muscle between stacks of sarcoplasmic reticulum (SR) cisternae and extensions of transverse-tubules (TT) that increase co-localization of proteins required for store-operated Ca 2+ entry (SOCE). (elifesciences.org)
- Importantly, this decrease in releasable Ca 2+ store content observed after exercise was reversed by repetitive high-frequency stimulation, consistent with enhanced SOCE. (elifesciences.org)
- Signaling of tumor-cells may further involve up-regulation of pore forming Ca 2+ channel protein Orai1, which accomplishes store operated Ca 2+ entry (SOCE). (biomedcentral.com)
- These currents are activated by interaction with ER-resident Ca 2+ sensor molecules STIM that translocate to plasma membrane-near regions in response to store depletion, inducing to store operated Ca 2+ entry (SOCE). (nature.com)
- Indeed, DT40 B cells stably over-expressing eYFP-Stim1 (Supplementary Fig. 1) displayed increased amplitude and period of SOCE relative to wild-type DT40 cells in response to either BCR activation, thapsigargin or cyclopiazonic acid (CPA) (Fig. 1a, Supplementary Fig. 2a). (mdm-inhibitors.com)
- Thapsigargin and CPA result in SOCE by inhibiting the SERCA pumps in the ER, thereby inducing passive launch of Ca2+ from your ER stores while bypassing proximal BCR signaling. (mdm-inhibitors.com)
- Increased SOCE leads to Ca2+-dependent Erk activation We examined the phosphotyrosine profile of Stim1-overexpressing DT40 B cells following thapsigargin activation for 2 and 5 minutes and observed robust and continual tyrosine phosphorylation of a ~42 kDa band, which was only modestly detectable in thapsigargin-stimulated wild-type DT40 cells (Fig. 1c). (mdm-inhibitors.com)
- 1-oleoyl-2-acetyl-sn-glycerol (OAG) causes an increase in NOX2 activity and has been shown to directly modulate Ca(2)(+) channels unrelated to the well-known store-operated Ca(2)(+) entry (SOCE) mechanism. (uni.lu)
SERCA1
- Since inhibition of SERCA is a mechanism of action that has been used to target solid tumors, thapsigargin has attracted research interest. (wikipedia.org)
Intracellular calcium stores3
- The Ca 2+ signal is characterized by a rapid increase in the concentration of free cytosolic calcium ([Ca 2+ ] i ) attributable to the opening of calcium channels located in the plasma membrane and in the membranes of intracellular calcium stores. (jneurosci.org)
- This inhibition was associated with deceleration of the recovery of depolarization-induced [Ca 2+ ] i transients, presumably due to the inhibition of Ca 2+ uptake by intracellular calcium stores. (uaeu.ac.ae)
- These results show that calcium-mobilizing GPCR agonists functionally interact with TNF-α to differentially regulate pro-inflammatory genes expression in human ASM cells, possibly by involving Tg-sensitive intracellular calcium stores, SOC and PKC. (tmu.edu.tw)
Mobilization4
- Shmigol, A , Kostyuk, P & Verkhratsky, A 1995, ' Dual action of thapsigargin on calcium mobilization in sensory neurons: Inhibition of Ca 2+ uptake by caffeine-sensitive pools and blockade of plasmalemmal Ca 2+ channels ', Neuroscience , vol. 65, no. 4, pp. 1109-1118. (uaeu.ac.ae)
- The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. (ox.ac.uk)
- The Ca2+ response was also inhibited when cells were incubated with a high concentration of ryanodine (200 microM), suggesting that Ca2+ mobilization is via a ryanodine-sensitive store. (ox.ac.uk)
- The presence of the store-operated Ca 2+ -channels in secretory cells of the lacrimal gland is confirmed by the observed increase of cellular Ca 2+ content as a result of Ca 2+ mobilization from the store by carbacholine or thapsigargin and following restoration of Ca 2+ concentration in the extracellular solution. (ukrbiochemjournal.org)
Receptors2
- Preclinical studies demonstrated that other effects of thapsigargin include suppression of nicotinic acetylcholine receptors activity in neurons of the guinea-pig ileum submucous plexus and rat superior cervical ganglion. (wikipedia.org)
- When both M-cholinergic receptors and P2Y receptors were activated Ca 2+ was released from the same IP 3 -sensitive store because the effects of ATP and carbacholine at high concentrations (1 mM/l and 10 µM/l, respectively) on the Ca 2+ content were non-additive. (ukrbiochemjournal.org)
Pump2
- Thapsigargin raises cytosolic (intracellular) calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. (wikipedia.org)
- It was initially described as a tumor promoting agent that induces rapid Ca 2+ release from intracellular stores 3 by the inhibition of the sarcoplasmic endoplasmic reticulm Ca 2+ -dependent ATPase pump without inositol phosphate formation 4 . (alomone.com)
Stimulation5
- As cell stimulation leads to both a partial Ca(2+) store depletion as well as the production of second messengers, these two pathways are problematic to distinguish. (unige.ch)
- Importantly, during voltage clamp recordings, histamine stimulation largely depleted the ER Ca(2+) store, explaining the activation of a CRAC-like current (due to store depletion) upon histamine in Ba(2+) medium. (unige.ch)
- In tracheal preparations subjected to depletion of intracellular stores of Ca2+ after repeated stimulation induced by carbachol in the presence of thapsigargin in medium without Ca2+, the EPJP reportedly inhibited the contraction induced by capacitive Ca2+ entry. (ndltd.org)
- Contraction linked to 5-HT(1B/1D) receptor stimulation in the rabbit renal artery can be explained by an influx of external Ca(2+) through voltage-dependent Ca(2+) channels and sensitization of the contractile myofilaments to existing levels of Ca(2+), with no release of Ca(2+) from intracellular stores. (ox.ac.uk)
- In addition, OAG potentiated the effect of fMLF on the activation of NOX2 and led to a discernible activity of NOX2 upon thapsigargin stimulation. (uni.lu)
Inositol2
- The release of Ca 2+ from intracellular stores through the inositol 1,4,5-trisphosphate receptor (InsP 3 R) occurs in both excitable and nonexcitable cells. (jneurosci.org)
- Mechanistic investigations revealed that through increasing the levels of intracellular reactive oxygen species (ROS), Gyp-L triggered protein ubiquitination and endoplasm reticulum (ER) stress response, leading to Ca 2+ release from ER inositol trisphosphate receptor (IP 3 R)-operated stores and finally cell death. (oncotarget.com)
Neurons7
- We have shown that calcium signaling is dramatically disturbed in HD76 neurons, specifically demonstrating higher levels of store-operated and voltage-gated calcium uptakes. (frontiersin.org)
- Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. (frontiersin.org)
- Our results are fully supportive in favor of the crucial role of calcium signaling deregulation in the HD pathogenesis and indicate that the cornerstone of excessive calcium uptake in HD-specific neurons is a calcium sensor and store-operated calcium channels activator STIM2, which should become a molecular target for medical treatment and novel neuroprotective drug development. (frontiersin.org)
- Decreased Ca 2+ release in aminergic neurons during development of the flight circuit can be compensated by reducing Ca 2+ uptake from the cytosol to intracellular stores. (jneurosci.org)
- The action of thapsigargin on intracellular calcium homeostasis and voltage-activated calcium currents was studied on freshly isolated adult mouse dorsal root ganglia neurons. (uaeu.ac.ae)
- Extracellular applications of thapsigargin at concentrations of 20-2000 nM did not cause substantial changes of basal [Ca 2+ ] i level in the majority of neurons studied. (uaeu.ac.ae)
- However, 5-10 min incubation of neurons with 20 nM thapsigargin completely and almost irreversibly inhibited caffeine-mediated Ca 2+ release from intracellular pools. (uaeu.ac.ae)
Apoptosis3
- Thapsigargin-induced depletion of Ca 2+ stores causes apoptosis in most cell lines 5 . (alomone.com)
- Consistent with a role for Ca2+ in antigen-induced apoptosis8, 10, Stim1 overexpression sensitized DT40 cells to both BCR- and thapsigargin-induced apoptosis (Fig. 1b). (mdm-inhibitors.com)
- Open in a separate window Physique 1 Sensitization of B cells to antigen-induced apoptosis correlates with Ca2+- dependent Erk activation(a) Intracellular Ca2+ measurements following activation with 1 M thapsigargin or the anti-BCR antibody M4. (mdm-inhibitors.com)
Extracellular1
- To confirm the identity of this protein, DT40 cells or Stim1-overexpressing DT40 cells were stimulated over time with thapsigargin or CPA in the presence or absence of extracellular Ca2+, and the phospho-Erk (pErk) responses were analyzed by circulation cytometry. (mdm-inhibitors.com)
Antibody2
- d) Phosphotyrosine-containing proteins were immunoprecipitated with the 4G10 antibody from lysates of thapsigargin-stimulated Stim1-overexpressing DT40 cells. (mdm-inhibitors.com)
- The antibody detects a 136 kDa* cleaved fragment corresponding to αII-Spectrin on SDS-PAGE immunoblots of mouse diaphram treated with thapsigargin. (ecmbio.com)
Inhibits1
- Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR. (wikipedia.org)
Cells12
- It is concluded that L-783,281 evokes [Ca 2+ ] i increases and exocytosis in β-cells via an IRS-1/PI3-K-dependent pathway and that the [Ca 2+ ] i increase involves release of Ca 2+ from intracellular stores. (diabetesjournals.org)
- DACT appeared to cause a selective decrease in caffeine-sensitive ryanodine receptor-operated calcium stores in LbetaT2 cells, rather than in thapsigargin-sensitive ER calcium stores. (cdc.gov)
- In endothelial cells, agonist-induced Ca(2+) entry takes place via the store-operated Ca(2+) entry pathway and/or via channel(s) gated by second messengers. (unige.ch)
- Ca2+ uptake and release properties of a thapsigargin-insensitive nonmitochondrial Ca2+ store in A7r5 and 16HBE14o- cells. (ac.be)
- We have examined the effect of overexpression of full-length TRPC1, depletion of endogenous TRPC1, and expression of TRPC1 in which the proposed pore region (S5-S6, amino acids (aa) 557-620) was deleted or modified by site-directed mutagenesis on thapsigargin- and carbachol-stimulated SOCC activity in HSG cells. (uthscsa.edu)
- Thus, in SH-SY5Y cells, opioids can mobilize Ca 2+ from intracellular stores but they require ongoing muscarinic receptor activation. (edu.au)
- Store-operated Ca 2+ entry mediated by STIM1-gated Orai1 channels is essential to activate immune cells and its inhibition or gain-of-function can lead to immune dysfunction and other pathologies. (nature.com)
- Error bars: s.e.m. (= 5 experiments) (c) Thapsigargin-stimulated cells were lysed and analyzed by immunoblotting with the phosphotyrosine antibodies 4G10 and RC20. (mdm-inhibitors.com)
- e) Thapsigargin-stimulated cells were analyzed by circulation cytometry for phospho-Erk (pErk) intensity. (mdm-inhibitors.com)
- Interference with the cytoskeleton also failed to affect the intracellular calcium signal that occurred when external calcium was re-admitted to cells in which the calcium stores had been previously depleted by exposure to thapsigargin/ionomycin in calcium-free external solution. (ox.ac.uk)
- Caffeine and Li+ did not affect the size of the intracellular Ca2+ signal that arose when external Ca2+ was re-admitted to cells which had been pre-exposed to thapsigargin/ionomycin in Ca2+-free external solution. (ox.ac.uk)
- Using thapsigargin (Tg), an agent that mobilizes calcium by directly emptying intracellular stores, we previously showed that intracellular calcium may play an important role in the regulation of intercellular adhesion molecule (ICAM)-1 gene expression induced by cytokines in human airway smooth muscle (ASM) cells. (tmu.edu.tw)
Concentration1
- Addition of OAG resulted in a rapid decrease of maximal intracellular Ca(2)(+) concentration induced by thapsigargin. (uni.lu)
Suppression1
- Since shRNA-mediated suppression of STIM2 decreased store-operated calcium uptake, we have speculated that high expression of STIM2 underlies the excessive entry through store-operated calcium channels in HD pathology. (frontiersin.org)
Influx3
- Store-depletion can secondarily activate plasma membrane calcium channels, allowing an influx of calcium into the cytosol. (wikipedia.org)
- The exact role of TRPC1 in store-operated calcium influx channel (SOCC) function is not known. (uthscsa.edu)
- Thapsigargin and ryanodine alone did not affect influx of Ca 2+ through voltage-gated Ca 2+ channels and inward currents evoked by Glu applications. (elsevierpure.com)
Ryanodine-sensitive1
- 4. Our results suggest that Ca 2+ release from internal stores, particularly from ryanodine-sensitive stores, is necessary for the induction of LTD in cultured PCs. (elsevierpure.com)
Increasing cytosolic1
- Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations and ER calcium depletion. (wikipedia.org)
Unfolded protein1
- Depletion of ER calcium stores leads to ER stress and activation of the unfolded protein response. (wikipedia.org)
Concentrations1
- At concentrations between 200 and 2000 nM, thapsigargin markedly depressed the amplitudes of depolarization-triggered [Ca 2+ ] i transients due to the inhibition of transmembrane Ca 2+ entry through voltage-activated Ca 2+ channels. (uaeu.ac.ae)
Entry2
- Unexpectedly, exercise also activated constitutive Ca 2+ entry coincident with a modest decrease in total releasable Ca 2+ store content. (elifesciences.org)
- OAG inhibited fMLF- and thapsigargin-induced Ca(2)(+) entry, a phenomenon that was not restored by protein kinase C (PKC) or PI3K blockade. (uni.lu)
Channels1
- Liu, X , Singh, BB & Ambudkar, IS 2003, ' TRPC1 is required for functional store-operated Ca 2+ channels: Role of acidic amino acid residues in the S5-S6 region ', Journal of Biological Chemistry , vol. 278, no. 13, pp. 11337-11343. (uthscsa.edu)
Agent1
- Thapsigargin (100 nM), an agent which discharges intracellular Ca 2+ stores, also blocked the opioid elevations of [Ca 2+ ](i). 9. (edu.au)
Activity3
- The biological activity has also attracted research into the laboratory synthesis of thapsigargin. (wikipedia.org)
- All three patterns of activity were dependent on the release of Ca 2+ from intracellular stores. (jneurosci.org)
- Thapsigargin Epoxide is a non-active analogue of Thapsigargin and can be used as a negative control for Thapsigargin activity 9,10 . (alomone.com)
Activation1
Cell2
- Used together these results provide proof that engagement from the anti-GRP78 autoantibodies with cell surface area GRP78 boosts TF PCA through a mechanism that involves the release of Ca2+ from ER stores. (healthcarecoremeasures.com)
- However, I(CRAC) was unaffected irrespective of whether cell ballooning occurred before or after depletion of stores. (ox.ac.uk)
Formation1
- It is not known whether the secondary modifications to the guaianolide occur before, or after the formation of thapsigargin, but will need to be considered when elucidating the true biosynthesis. (wikipedia.org)
Treatment1
- A prodrug of thapsigargin, mipsagargin, is currently undergoing clinical trials for the treatment of glioblastoma. (wikipedia.org)