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101.
Endogenously bound calmodulin is essential for the function of the inositol 1,4,5-trisphosphate receptor 总被引:1,自引:0,他引:1
Kasri NN Török K Galione A Garnham C Callewaert G Missiaen L Parys JB De Smedt H 《The Journal of biological chemistry》2006,281(13):8332-8338
Calmodulin (CaM) is a ubiquitous Ca2+ sensor protein that plays an important role in regulating a large number of Ca2+ channels, including the inositol 1,4,5-trisphosphate receptor (IP3R). Despite many efforts, the exact mechanism by which CaM regulates the IP3R still remains elusive. Here we show, using unidirectional 45Ca2+ flux experiments on permeabilized L15 fibroblasts and COS-1 cells, that endogenously bound CaM is essential for the proper activation of the IP3R. Removing endogenously bound CaM by titration with a high affinity (pM) CaM-binding peptide derived from smooth muscle myosin light-chain kinase (MLCK peptide) strongly inhibited IP3-induced Ca2+ release. This inhibition was concentration- and time-dependent. Removing endogenously bound CaM affected the maximum release capacity but not its sensitivity to IP3. A mutant peptide with a strongly reduced affinity for CaM did not affect inhibited IP3-induced Ca2+ release. Furthermore, the inhibition by the MLCK peptide was fully reversible. Re-adding exogenous CaM, but not CaM1234, reactivated the IP3R. These data suggest that, by using a specific CaM-binding peptide, we removed endogenously bound CaM from a high affinity CaM-binding site on the IP3R, and this resulted in a complete loss of the IP3R activity. Our data support a new model whereby CaM is constitutively associated with the IP3R and functions as an essential subunit for proper functioning of the IP3R. 相似文献
102.
The suppressor domain of inositol 1,4,5-trisphosphate receptor plays an essential role in the protection against apoptosis 总被引:1,自引:0,他引:1
The N-terminal 1-225 amino acids (aa) of the type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1) function as a suppressor/coupling domain. In this study we used IP(3)R-deficient B-lymphocytes to investigate the effects of modifications in this domain on IP(3) binding and Ca(2+)-release activity. Although the N-terminal 1-225 aa of IP(3)R3 had the same role as in IP(3)R1, the suppression of IP(3) binding for IP(3)R1 was lost when the suppressor/coupling domains were exchanged between the two isoforms. Resulting chimeric receptors showed a higher sensitivity to IP(3)-induced activation (IICR). Deletion of 11 aa in IP(3)R1 ([Delta76-86]-IP(3)R1) or replacing aa 76-86 of the IP(3)R1 in the suppressor/coupling domain by 13 aa of IP(3)R3 ([75-87 T3]-IP(3)R1) also resulted in increased IP(3) binding and sensitivity of IICR. These residues constitute the only part of the suppressor/coupling domain that is strikingly different between the two isoforms. Expression of [Delta76-86]-IP(3)R1 and of [75-87 T3]-IP(3)R1 increased the propensity of cells to undergo staurosporine-induced apoptosis, but had no effect on the Ca(2+) content in the endoplasmic reticulum. In the cell model used, our observations suggest that the sensitivity of the Ca(2+)-release activity of IP(3)R1 to IP(3) influences the sensitivity of the cells to apoptotic stimuli and that the suppressor/coupling domain may have an anti-apoptotic function by attenuating the sensitivity of IICR. 相似文献
103.
A dual role for Ca(2+) in autophagy regulation 总被引:1,自引:0,他引:1
Autophagy is a cellular process responsible for delivery of proteins or organelles to lysosomes. It participates not only in maintaining cellular homeostasis, but also in promoting survival during cellular stress situations. It is now well established that intracellular Ca2+ is one of the regulators of autophagy. However, this control of autophagy by intracellular Ca2+ signaling is the subject of two opposite views. On the one hand, the available evidence indicates that intracellular Ca2+ signals, and mainly inositol 1,4,5-trisphosphate receptors (IP3Rs), suppress autophagy. On the other hand, elevated cytosolic Ca2+ concentrations ([Ca2+]cyt) were also shown to promote the autophagic process. Here, we will provide a critical overview of the literature and discuss both hypotheses. Moreover, we will suggest a model explaining how changes in intracellular Ca2+ signaling can lead to opposite outcomes, depending on the cellular state. 相似文献
104.
Jean-Paul DecuypereGiovanni Monaco Geert BultynckLudwig Missiaen Humbert De SmedtJan B. Parys 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2011,1813(5):1003-1013
The amount of Ca2+ taken up in the mitochondrial matrix is a crucial determinant of cell fate; it plays a decisive role in the choice of the cell between life and death. The Ca2+ ions mainly originate from the inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ stores of the endoplasmic reticulum (ER). The uptake of these Ca2+ ions in the mitochondria depends on the functional properties and the subcellular localization of the IP3 receptor (IP3R) in discrete domains near the mitochondria. To allow for an efficient transfer of the Ca2+ ions from the ER to the mitochondria, structural interactions between IP3Rs and mitochondria are needed. This review will focus on the key proteins involved in these interactions, how they are regulated, and what are their physiological roles in apoptosis, necrosis and autophagy. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. 相似文献
105.
Giovanni Monaco Elke Decrock Nir Arbel Alexander R. van Vliet Rita M. La Rovere Humbert De Smedt Jan B. Parys Patrizia Agostinis Luc Leybaert Varda Shoshan-Barmatz Geert Bultynck 《The Journal of biological chemistry》2015,290(14):9150-9161
Excessive Ca2+ fluxes from the endoplasmic reticulum to the mitochondria result in apoptotic cell death. Bcl-2 and Bcl-XL proteins exert part of their anti-apoptotic function by directly targeting Ca2+-transport systems, like the endoplasmic reticulum-localized inositol 1,4,5-trisphosphate receptors (IP3Rs) and the voltage-dependent anion channel 1 (VDAC1) at the outer mitochondrial membranes. We previously demonstrated that the Bcl-2 homology 4 (BH4) domain of Bcl-2 protects against Ca2+-dependent apoptosis by binding and inhibiting IP3Rs, although the BH4 domain of Bcl-XL was protective independently of binding IP3Rs. Here, we report that in contrast to the BH4 domain of Bcl-2, the BH4 domain of Bcl-XL binds and inhibits VDAC1. In intact cells, delivery of the BH4-Bcl-XL peptide via electroporation limits agonist-induced mitochondrial Ca2+ uptake and protects against staurosporine-induced apoptosis, in line with the results obtained with VDAC1−/− cells. Moreover, the delivery of the N-terminal domain of VDAC1 as a synthetic peptide (VDAC1-NP) abolishes the ability of BH4-Bcl-XL to suppress mitochondrial Ca2+ uptake and to protect against apoptosis. Importantly, VDAC1-NP did not affect the ability of BH4-Bcl-2 to suppress agonist-induced Ca2+ release in the cytosol or to prevent apoptosis, as done instead by an IP3R-derived peptide. In conclusion, our data indicate that the BH4 domain of Bcl-XL, but not that of Bcl-2, selectively targets VDAC1 and inhibits apoptosis by decreasing VDAC1-mediated Ca2+ uptake into the mitochondria. 相似文献
106.
The effect of lead on photosynthesis and respiration in detached leaves and in mesophyll protoplasts of Pisum sativum 总被引:2,自引:0,他引:2
Eugeniusz Parys Elżbieta Romanowska Maria Siedlecka Jerzy W. Poskuta 《Acta Physiologiae Plantarum》1998,20(3):313-322
Photosynthesis and transpiration rate of detached leaves of pea (Pisum sativum L. cv. Iłowiecki) exposed to solution of Pb(NO3)2 at 1 or 5 mmol·dm−3 concentrations were inhibited. The higher concentration of this toxicant decreased photosynthesis and transpiration rates
2 and 3 times respectively, and increased respiration by about 20 %, as measured after 24 hours of treatment. Similarly to
Pb(NO3)2, glyceraldehyde solution, an inhibitor of phosphoribulokinase, at 50 mmol·dm−3 concentration decreased the rates of photosynthesis and transpiration during introduction into pea leaves. The rate of dark
respiration, however, remained unchanged during 2 hours of experiment.
The potential photochemical efficiency of PS II (Fv/Fm) and the activity of Rubisco (EC 4.1.1.39) at 5 mmol·dm−3 of Pb(NO3)2 were lowered by 10 % and 20 % respectively, after 24 hours. Neither changes in the activity of PEPC (EC 4.1.1.31) or protein
and pigment contents were noted in Pb-treated leaves. The photosynthetic activity of protoplasts isolated from leaves treated
for 24 or 48 hours with Pb(NO3)2 at 5 mmol·dm−3 concentration was decreased 10 % or 25 %, whereas, the rate of dark respiration was stimulated by about 40 % and 75 %, respectively.
The content of abscisic acid, a hormone responsible for stomatal closure, in detached pea leaves treated for 24 h with 5 mmol·dm−3 of Pb(NO3)2 solution was increased by about 3 times; a longer (48h) treatment led to further increase (by about 7 times) in the amount
of this hormone. The results of our experiments provide evidences that CO2 fixation in detached pea leaves, at least up to 24 hours of Pb(NO3)2 treatment, was restricted mainly by stomatal closure. 相似文献
107.
Lockyer PJ Vanlingen S Reynolds JS McNulty TJ Irvine RF Parys JB Cullen PJ 《Biochemical and biophysical research communications》1999,255(2):421-426
GAP1(IP4BP) and GAP1(m) belong to the GAP1 family of Ras GTPase-activating proteins that are candidate InsP4 receptors. Here we show they are ubiquitously expressed in human tissues and are likely to have tissue-specific splice variants. Analysis by subcellular fractionation of RBL-2H3 rat basophilic leukemia cells confirms that endogenous GAP1(IP4BP) is primarily localised to the plasma membrane, whereas GAP1(m) appears localised to the cytoplasm (cytosol and internal membranes) but not the plasma membrane. Subcellular fractionation did not indicate a specific co-localisation between membrane-bound GAP1(m) and several Ca2+ store markers, consistent with the lack of co-localisation between GAP1(m) and SERCA1 upon co-expression in COS-7 cells. This difference suggests that GAP1(m) does not reside at a site where it could regulate the ability of InsP4 to release intracellular Ca2+. As GAP1(m) is primarily localised to the cytosol of unstimulated cells it may be spatially regulated in order to interact with Ras at the plasma membrane. 相似文献
108.
Verbert L Lee B Kocks SL Assefa Z Parys JB Missiaen L Callewaert G Fissore RA De Smedt H Bultynck G 《Biology of the cell / under the auspices of the European Cell Biology Organization》2008,100(1):39-49
Background information. The IP3R (inositol 1,4,5‐trisphosphate receptor) is a tetrameric channel that accounts for a large part of the intracellular Ca2+ release in virtually all cell types. We have previously demonstrated that caspase‐3‐mediated cleavage of IP3R1 during cell death generates a C‐terminal fragment of 95 kDa comprising the complete channel domain. Expression of this truncated IP3R increases the cellular sensitivity to apoptotic stimuli, and it was postulated to be a constitutively active channel. Results. In the present study, we demonstrate that expression of the caspase‐3‐cleaved C‐terminus of IP3R1 increased the rate of thapsigargin‐mediated Ca2+ leak and decreased the rate of Ca2+ uptake into the ER (endoplasmic reticulum), although it was not sufficient by itself to deplete intracellular Ca2+ stores. We detected the truncated IP3R1 in different cell types after a challenge with apoptotic stimuli, as well as in aged mouse oocytes. Injection of mRNA corresponding to the truncated IP3R1 blocked sperm factor‐induced Ca2+ oscillations and induced an apoptotic phenotype. Conclusions. In the present study, we show that caspase‐3‐mediated truncation of IP3R1 enhanced the Ca2+ leak from the ER. We suggest a model in which, in normal conditions, the increased Ca2+ leak is largely compensated by enhanced Ca2+‐uptake activity, whereas in situations where the cellular metabolism is compromised, as occurring in aging oocytes, the Ca2+ leak acts as a feed‐forward mechanism to divert the cell into apoptosis. 相似文献
109.
Bultynck G Vermassen E Szlufcik K De Smet P Fissore RA Callewaert G Missiaen L De Smedt H Parys JB 《Biochemical and biophysical research communications》2003,311(4):1181-1193
The Ca(2+)- and calmodulin-dependent phosphatase calcineurin was reported to interact with the inositol 1,4,5-trisphosphate receptor (IP(3)R) and the ryanodine receptor (RyR) and to modulate their phosphorylation status and activity. However, controversial data on the molecular mechanisms involved and on the functional relevance of calcineurin for these channel-complexes have been described. Hence, we will focus on the functional importance of calcineurin for IP(3)R and RyR function and on the different mechanisms by which Ca(2+)-dependent dephosphorylation can affect the gating of those intracellular Ca(2+)-release channels. Since many studies made use of immunosuppressive drugs that are inhibiting calcineurin activity, we will also have to take the different side effects of these drugs into account for the proper interpretation of the effects of calcineurin on intracellular Ca(2+)-release channels. In addition, it became recently known that various other phosphatases and kinases can associate with these channels, thereby forming macromolecular complexes. The relevance of these enzymes for IP(3)R and RyR functioning will be reviewed since in some cases they could interfere with the effects ascribed to calcineurin. Finally, we will discuss the downstream effects of calcineurin on the regulation of the expression levels of intracellular Ca(2+)-release channels as well as the relation between IP(3)R- and RyR-mediated Ca(2+) release and calcineurin-dependent gene expression. 相似文献
110.
We have investigated how the immunosuppressant drug FK506 affected the basal Ca(2+) leak in permeabilized A7r5 cells. Non-mitochondrial Ca(2+) stores loaded to steady state with Ca(2+) slowly lost their accumulated Ca(2+) during incubation in a Ca(2+)-free efflux medium. FK506 up to 100 microM had no effect on the basal Ca(2+) leak. In contrast, the rate of Ca(2+) release proceeded much faster immediately after washing out FK506. The increase in rate of Ca(2+) release after washing out of this compound depended on both its initial concentration and on the time of pre-incubation. A similar effect was also observed after removing another immunosuppressant drug (rapamycin) and after removing the inositol 1,4,5-trisphosphate receptor inhibitor xestospongin C. Since all these substances have a high octanol/H(2)O partition coefficient and accumulate in the endoplasmic reticulum membrane, we suggest that the transient increase in the basal Ca(2+) leak is due to the sudden removal of these lipophilic substances from the membrane. 相似文献