Academic literature on the topic 'IP3R3'
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Journal articles on the topic "IP3R3"
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Foulon, Arthur, Pierre Rybarczyk, Nicolas Jonckheere, Eva Brabencova, Henri Sevestre, Halima Ouadid-Ahidouch, and Lise Rodat-Despoix. "Inositol (1,4,5)-Trisphosphate Receptors in Invasive Breast Cancer: A New Prognostic Tool?" International Journal of Molecular Sciences 23, no. 6 (March 9, 2022): 2962. http://dx.doi.org/10.3390/ijms23062962.
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Breast cancer is the leading cause of cancer death among women in worldwide and France. The disease prognosis and treatment differ from one breast cancer subtype to another, and the disease outcome depends on many prognostic factors. Deregulation of ion flux (especially Ca2+ flux) is involved in many pathophysiology processes, including carcinogenesis. Inside the cell, the inositol-trisphosphate receptor (IP3R) is a major player in the regulation of the Ca2+ flux from the endoplasmic reticulum to the cytoplasm. The IP3Rs (and particularly the IP3R3 subtype) are known to be involved in proliferation, migration, and invasion processes in breast cancer cell lines. The objective of the present study was to evaluate the potential value of IP3Rs as prognostic biomarkers in breast cancer. We found that expression levels of IP3R3 and IP3R1 (but not IP3R2) were significantly higher in invasive breast cancer of no special type than in non-tumor tissue from the same patient. However, the IP3R3 subtype was expressed more strongly than the IP3R1 and IP3R2 subtypes. Furthermore, the expression of IP3R3 (but not of IP3R1 or IP3R2) was positively correlated with prognostic factors such as tumor size, regional node invasion, histologic grade, proliferation index, and hormone receptor status. In an analysis of public databases, we found that all IP3Rs types are significantly associated with overall survival and progression-free survival in patients with breast cancer. We conclude that relative to the other two IP3R subtypes, IP3R3 expression is upregulated in breast cancer and is correlated with prognostic factors.
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Lee, Su Youn, Hee-Seop Yoo, Hye-Seung Choi, Ka Young Chung, and Min-Duk Seo. "Structural and dynamic insights into the subtype-specific IP3-binding mechanism of the IP3 receptor." Biochemical Journal 473, no. 20 (October 11, 2016): 3533–43. http://dx.doi.org/10.1042/bcj20160539.
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There are three subtypes of vertebrate inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), a Ca2+-release channel on the ER membrane — IP3R1, IP3R2, and IP3R3 — each of which has a distinctive role in disease development. To determine the subtype-specific IP3-binding mechanism, we compared the thermodynamics, thermal stability, and conformational dynamics between the N-terminal regions of IP3R1 (IP3R1-NT) and IP3R3 (IP3R3-NT) by performing circular dichroism (CD), isothermal titration calorimetry (ITC), and hydrogen–deuterium exchange mass spectrometry (HDX-MS). Previously determined crystal structures of IP3R1-NT and HDX-MS results from this study revealed that both IP3R1 and IP3R3 adopt a similar IP3-binding mechanism. However, several regions, including the α- and β-interfaces, of IP3R1-NT and IP3R3-NT show significantly different conformational dynamics upon IP3 binding, which may explain the different IP3-binding affinities between the subtypes. The importance of the interfaces for subtype-specific IP3 binding is also supported by the different dynamic conformations of the two subtypes in the apo-states. Furthermore, IP3R1-NT and IP3R3-NT show different IP3-binding affinities and thermal stabilities, but share similar thermodynamic properties for IP3 binding. These results collectively provide new insights into the mechanism underlying IP3 binding to IP3Rs and the subtype-specific regulatory mechanism.
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NAGALEEKAR, VISWAS K., SEAN DIEHL, Ignacio Juncadella, Colette Charland, Lee Ann Garrett-Sinha, Natarajan Muthusamy, Juan Anguita, and Mercedes Rincón. "Ets1-dependent IP3R3 expression in naïve CD4+ T cells is required for cytokine gene expression (87.22)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S132. http://dx.doi.org/10.4049/jimmunol.178.supp.87.22.
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Abstract IP3 receptors (IP3Rs) are critical for the release of Ca++ from intracellular stores in response to IP3 generated upon T cell receptor (TCR) ligation. However, little is known about the expression of the different IP3Rs in CD4+ T cells and their contribution to cytokine gene expression during antigen stimulation. Here, we show for the first time that prior to activation, naïve CD4+ T cells only express IP3R3, but not IP3R1 and IP3R2. IP3R3-mediated Ca++ flux for cytokine gene expression is required for an extended period of time on the order of hours that varies for specific cytokine. IP3R3 gene expression in CD4+ T cells is dependent on the transcription factor Ets1 and is downregulated during the activation due to the loss of this transcription factor. The downregulation of IP3R3 in activated cells correlates with the failure of TCR ligation to trigger intracellular Ca++ mobilization in these cells. Thus, IP3R3 plays an important role in cytokine gene expression during early activation of naïve CD4+ T cells.
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Khan, Samir A., Ana M. Rossi, Andrew M. Riley, Barry V. L. Potter, and Colin W. Taylor. "Subtype-selective regulation of IP3 receptors by thimerosal via cysteine residues within the IP3-binding core and suppressor domain." Biochemical Journal 451, no. 2 (March 28, 2013): 177–84. http://dx.doi.org/10.1042/bj20121600.
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IP3R (IP3 [inositol 1,4,5-trisphosphate] receptors) and ryanodine receptors are the most widely expressed intracellular Ca2+ channels and both are regulated by thiol reagents. In DT40 cells stably expressing single subtypes of mammalian IP3R, low concentrations of thimerosal (also known as thiomersal), which oxidizes thiols to form a thiomercurylethyl complex, increased the sensitivity of IP3-evoked Ca2+ release via IP3R1 and IP3R2, but inhibited IP3R3. Activation of IP3R is initiated by IP3 binding to the IBC (IP3-binding core; residues 224–604) and proceeds via re-arrangement of an interface between the IBC and SD (suppressor domain; residues 1–223). Thimerosal (100 μM) stimulated IP3 binding to the isolated NT (N-terminal; residues 1–604) of IP3R1 and IP3R2, but not to that of IP3R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP3) to NT1 was unaffected by thiomersal, suggesting that the effect of thimerosal is specifically related to IP3R activation. IP3 binding to NT1 in which all cysteine residues were replaced by alanine was insensitive to thimerosal, so too were NT1 in which cysteine residues were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with cysteine in both the SD and IBC. Chimaeric proteins in which the SD of the IP3R was replaced by the structurally related A domain of a ryanodine receptor were functional, but thimerosal inhibited both IP3 binding to the chimaeric NT and IP3-evoked Ca2+ release from the chimaeric IP3R. This is the first systematic analysis of the effects of a thiol reagent on each IP3R subtype. We conclude that thimerosal selectively sensitizes IP3R1 and IP3R2 to IP3 by modifying cysteine residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor.
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HIROTA, Junji, Masashi BABA, Mineo MATSUMOTO, Teiichi FURUICHI, Kiyoshi TAKATSU, and Katsuhiko MIKOSHIBA. "T-cell-receptor signalling in inositol 1,4,5-trisphosphate receptor (IP3R) type-1-deficient mice: is IP3R type 1 essential for T-cell-receptor signalling?" Biochemical Journal 333, no. 3 (August 1, 1998): 615–19. http://dx.doi.org/10.1042/bj3330615.
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Stimulation of T-cells via the T-cell receptor (TCR) complex is accompanied by an increase in intracellular Ca2+ concentration ([Ca2+]i). Recently, it was reported that a stable transformant of the human T-cell line, Jurkat, expressing an antisense cDNA construct of inositol 1,4,5-trisphosphate receptor (IP3R) type 1 (IP3R1), failed to demonstrate increased [Ca2+]i or interleukin-2 production after TCR stimulation and was also resistant to apoptotic stimuli. This cell line lacked IP3R1 expression, but expressed the type-2 and -3 receptors, IP3R2 and IP3R3 respectively [Jayaraman, Ondriasova, Ondrias, Harnick and Marks (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 6007–6011, and Jayaraman and Marks (1997) Mol. Cell. Biol. 17, 3005–3012]. The authors concluded that IP3R1 is essential for TCR signalling and suggested that Ca2+ release via IP3R1 is a critical mediator of apoptosis. To establish whether a loss of IP3R1 function in T-cells occurred in vivo and in vitro, we investigated Ca2+ signalling after TCR stimulation and the properties of T-cells using IP3R1-deficient (IP3R1-/-) mice. As IP3R1-/- mice die at weaning, we transplanted bone marrow cells of IP3R1-/- mice into irradiated wild-type mice. Western blot analysis showed that the recipient IP3R1-containing (IP3R1+/+) lymphocytes were replaced by the donor IP3R1-/- lymphocytes after transplantation and that expression of IP3R2 and IP3R3 was unaltered. In contrast with the previous reports, T-cells lacking IP3R1 were able to mobilize Ca2+ from intracellular Ca2+ stores after stimulation via the TCR. We observed no significant differences between IP3R1+/+ and IP3R1-/- T-cells in terms of the number of thymocytes and splenocytes, the proportion of the T-cell phenotype, proliferative response to anti-CD3 monoclonal antibody (mAb) stimulation and cell viability. Therefore IP3R1 is not essential for T-cell development and function.
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Mikoshiba, Katsuhiko. "The IP3 receptor/Ca2+ channel and its cellular function." Biochemical Society Symposia 74 (January 12, 2007): 9–22. http://dx.doi.org/10.1042/bss2007c02.
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The IP3R [IP3 (inositol 1,4,5-trisphosphate) receptor] is responsible for Ca2+ release from the ER (endoplasmic reticulum). We have been working extensively on the P400 protein, which is deficient in Purkinje-neuron-degenerating mutant mice. We have discovered that P400 is an IP3R and we have determined the primary sequence. Purified IP3R, when incorporated into a lipid bilayer, works as a Ca2+ release channel and overexpression of IP3R shows enhanced IP3 binding and channel activity. Addition of an antibody blocks Ca2+ oscillations indicating that IP3R1 works as a Ca2+ oscillator. Studies on the role of IP3R during development show that IP3R is involved in fertilization and is essential for determination of dorso-ventral axis formation. We found that IP3R is involved in neuronal plasticity. A double homozygous mutant of IP3R2 (IP3R type 2) and IP3R3 (IP3R type 3) shows a deficit of saliva secretion and gastric juice secretion suggesting that IP3Rs are essential for exocrine secretion. IP3R has various unique properties: cryo-EM (electron microscopy) studies show that IP3R contains multiple cavities; IP3R allosterically and dynamically changes its form reversibly (square form–windmill form); IP3R is functional even though it is fragmented by proteases into several pieces; the ER forms a meshwork but also forms vesicular ER and moves along microtubules using a kinesin motor; X ray analysis of the crystal structure of the IP3 binding core consists of an N-terminal β-trefoil domain and a C-terminal α-helical domain. We have discovered ERp44 as a redox sensor in the ER which binds to the luminal part of IP3R1 and regulates its activity. We have also found the role of IP3 is not only to release Ca2+ but also to release IRBIT which binds to the IP3 binding core of IP3R.
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MORITA, Takao, Akihiko TANIMURA, Akihiro NEZU, Tomohiro KUROSAKI, and Yosuke TOJYO. "Functional analysis of the green fluorescent protein-tagged inositol 1,4,5-trisphosphate receptor type 3 in Ca2+ release and entry in DT40 B lymphocytes." Biochemical Journal 382, no. 3 (September 7, 2004): 793–801. http://dx.doi.org/10.1042/bj20031970.
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We examined the function of GFP-IP3R3 (green fluorescent protein-tagged inositol 1,4,5-trisphosphate receptor type 3) in Ca2+ release and entry using a mutant DT40 cell line (IP3R-KO) in which all three IP3R genes had been disrupted. GFP-IP3R3 fluorescence largely overlapped with the distribution of endoplasmic reticulum, whereas a portion of GFP-IP3R3 apparently co-localized with the plasma membrane. The application of IP3 to permeabilized WT (wild-type) DT40 cells induced Ca2+ release from internal stores. Although this did not occur in IP3R-KO cells it was restored by expression of GFP-IP3R3. In intact cells, application of anti-IgM, an activator of the BCR (B-cell receptor), or trypsin, a protease-activated receptor 2 agonist, did not cause any Ca2+ response in IP3R-KO cells, whereas these treatments induced oscillatory or transient Ca2+ responses in GFP-IP3R3-expressing IP3R-KO cells, as well as in WT cells. In addition, BCR activation elicited Ca2+ entry in WT and GFP-IP3R3-expressing IP3R-KO cells but not in IP3R-KO cells. This BCR-mediated Ca2+ entry was observed in the presence of La3+, which blocks capacitative Ca2+ entry. Thapsigargin depleted Ca2+ stores and led to Ca2+ entry in IP3R-KO cells irrespective of GFP-IP3R3 expression. In contrast with BCR stimulation, thapsigargin-induced Ca2+ entry was completely blocked by La3+, suggesting that the BCR-mediated Ca2+ entry pathway is distinct from the capacitative Ca2+ entry pathway. The present study demonstrates that GFP-IP3R3 could compensate for native IP3R in both IP3-induced Ca2+ release and BCR-mediated Ca2+ entry.
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Yue, Lili, Liuqing Wang, Yangchun Du, Wei Zhang, Kozo Hamada, Yoshifumi Matsumoto, Xi Jin, et al. "Type 3 Inositol 1,4,5-Trisphosphate Receptor is a Crucial Regulator of Calcium Dynamics Mediated by Endoplasmic Reticulum in HEK Cells." Cells 9, no. 2 (January 22, 2020): 275. http://dx.doi.org/10.3390/cells9020275.
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Being the largest the Ca2+ store in mammalian cells, endoplasmic reticulum (ER)-mediated Ca2+ signalling often involves both Ca2+ release via inositol 1, 4, 5-trisphosphate receptors (IP3R) and store operated Ca2+ entries (SOCE) through Ca2+ release activated Ca2+ (CRAC) channels on plasma membrane (PM). IP3Rs are functionally coupled with CRAC channels and other Ca2+ handling proteins. However, it still remains less well defined as to whether IP3Rs could regulate ER-mediated Ca2+ signals independent of their Ca2+ releasing ability. To address this, we generated IP3Rs triple and double knockout human embryonic kidney (HEK) cell lines (IP3Rs-TKO, IP3Rs-DKO), and systemically examined ER Ca2+ dynamics and CRAC channel activity in these cells. The results showed that the rate of ER Ca2+ leakage and refilling, as well as SOCE were all significantly reduced in IP3Rs-TKO cells. And these TKO effects could be rescued by over-expression of IP3R3. Further, results showed that the diminished SOCE was caused by NEDD4L-mediated ubiquitination of Orai1 protein. Together, our findings indicate that IP3R3 is one crucial player in coordinating ER-mediated Ca2+ signalling.
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Song, Tengyao, Qiongyu Hao, Yun-Min Zheng, Qing-Hua Liu, and Yong-Xiao Wang. "Inositol 1,4,5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 12 (December 15, 2015): L1455—L1466. http://dx.doi.org/10.1152/ajplung.00148.2015.
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Transient receptor potential-3 (TRPC3) channels play a predominant role in forming nonselective cation channels (NSCCs) in airway smooth muscle cells (ASMCs) and are significantly increased in their activity and expression in asthmatic ASMCs. To extend these novel findings, we have explored the regulatory mechanisms that control the activity of TRPC3 channels. Our data for the first time reveal that inositol 1,4,5-trisphosphate (IP3), an important endogenous signaling molecule, can significantly enhance the activity of single NSCCs in ASMCs. The analog of diacylglycerol (DAG; another endogenous signaling molecule), 1-oleyl-2-acetyl- sn-glycerol (OAG), 1-stearoyl-2-arachidonoyl- sn-glycerol (SAG), and 1-stearoyl-2-linoleoyl- sn-glycerol (SLG) all augment NSCC activity. The effects of IP3 and OAG are fully abolished by lentiviral short-hairpin (sh)RNA-mediated TRPC3 channel knockdown (KD). The stimulatory effect of IP3 is eliminated by heparin, an IP3 receptor (IP3R) antagonist that blocks the IP3-binding site, but not by xestospongin C, the IP3R antagonist that has no effect on the IP3-binding site. Lentiviral shRNA-mediated KD of IP3R1, IP3R2, or IP3R3 does not alter the excitatory effect of IP3. TRPC3 channel KD greatly inhibits IP3-induced increase in intracellular Ca2+ concentration. IP3R1 KD produces a similar inhibitory effect. TRPC3 channel and IP3R1 KD both diminish the muscarinic receptor agonist methacholine-evoked Ca2+ responses. Taking these findings together, we conclude that IP3, the important intracellular second messenger, may activate TRPC3 channels to cause extracellular Ca2+ influx, in addition to opening IP3Rs to induce intracellular Ca2+ release. This novel extracellular Ca2+ entry route may play a significant role in mediating IP3-mediated numerous cellular responses in ASMCs and other cells.
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BULTYNCK, Geert, Patrick DE SMET, Daniela ROSSI, Geert CALLEWAERT, Ludwig MISSIAEN, Vincenzo SORRENTINO, Humbert DE SMEDT, and Jan B. PARYS. "Characterization and mapping of the 12kDa FK506-binding protein (FKBP12)-binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor." Biochemical Journal 354, no. 2 (February 22, 2001): 413–22. http://dx.doi.org/10.1042/bj3540413.
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We investigated the interaction of the 12kDa FK506-binding protein (FKBP12) with two ryanodine-receptor isoforms (RyR1 and RyR3) and with two myo-inositol 1,4,5-trisphosphate (IP3) receptor isoforms (IP3R1 and IP3R3). Using glutathione S-transferase (GST)-FKBP12 affinity chromatography, we could efficiently extract RyR1 (42±7% of the solubilized RyR1) from terminal cisternae of skeletal muscle as well as RyR3 (32±4% of the solubilized RyR3) from RyR3-overexpressing HEK-293 cells. These interactions were completely abolished by FK506 (20µM) but were largely unaffected by RyR-channel modulators. In contrast, neither IP3R1 nor IP3R3 from various sources, including rabbit cerebellum, A7r5 smooth-muscle cells and IP3R-overexpressing Sf9 insect cells from Spodoptera frugiperda, were retained on the GST-FKBP12 matrix. Moreover, immunoprecipitation experiments indicated a high-affinity interaction of FKBP12 with RyR1 but not with IP3R1. In order to determine the FKBP12-binding site, we fragmented both RyR1 and IP3R1 by limited proteolysis. We obtained a 45kDa fragment of RyR1 that bound to the GST-FKBP12 matrix, indicating that it retained all requirements for FKBP12 binding. This fragment was identified by its interaction with antibody m34C and must therefore contain its epitope (amino acids 2756–2803). However, no fragment of IP3R1 was retained on the column. These molecular data are in agreement with the lack of correlation between FKBP12 and IP3R1 expression in various cell types. The observation that FKBP12 did not affect IP3-induced Ca2+ release but reduced caffeine-induced Ca2+ release also indicated that mature IP3R1 and IP3R3, in contrast to RyR1 and RyR3, did not display a specific, high-affinity interaction with FKBP12.
Dissertations / Theses on the topic "IP3R3"
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CORLIANÒ, VALERIA. "LPS-dependent NFAT activation in dendritic cells is regulated by IP4-mediated calcium entry through plasma membrane IP3R3." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199025.
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Le cellule mieloidi del sistema immunitario innato sono in grado di riconoscere microbi o prodotti microbici attraverso recettori per i profili molecolari (PRRs, pattern recognition receptors). Tra questi, i recettori Toll-like (TLRs, Toll-like receptors) sono quelli più estensivamente caratterizzati. Il TLR4, insieme alle proteine CD14 e MD-2, forma il complesso multi-recettoriale che riconosce il Lipopolisaccaride (LPS), principale componente della membrana esterna dei batteri Gram-negativi. Il CD14 concentra il segnale dell’LPS e media la rilocalizzazione di TLR4 e MD-2 all’interno dell’endosoma. In seguito ad un’esposizione acuta ad LPS, il CD14, indipendentemente dal TLR4, attiva la via di trasduzione del segnale di NFAT attraverso chinasi della famiglia src e l’attivazione della PLCγ2 che portano ad un rapido ingresso di Ca2+ e all’attivazione della proteina calcineurina. Questa funzione del CD14 è cellula-specifica, essendo attiva nelle cellule dendritiche (DCs, dendritic cells) e non nei macrofagi. In questo lavoro abbiamo studiato il meccanismo di mobilizzazione del Ca2+ nelle DCs e abbiamo proposto una spiegazione per la mancata attivazione della via di trasduzione del segnale di CD14/NFAT nei macrofagi in risposta all’LPS.
È stato dimostrato che, sia in DCs murine che in una sottopopolazione di DCs umane CD14+ recentemente descritta, il recettore di tipo 3 dell’IP3 (IP3R3) è espresso non soltanto in compartimenti intracellulari, quali il reticolo endoplasmatico (ER, endoplasmic reticulum) ma anche a livello della membrana plasmatica (PM, plasma membrane) e, in modo interessante, colocalizza con il CD14 nelle zattere lipidiche (lipid rafts). È stato riscontrato che, la mobilizzazione del Ca2+ nelle DCs stimolate con l’LPS è dovuto ad un flusso diretto di Ca2+ dallo spazio extracellulare che dipende dall’IP3R3 e richiede l’IP4, piuttosto che l’IP3, come secondo messaggero. Infatti, il silenziamento dell’IP3R3 o l’inibizione dell’ITPKB, la chinasi che converte l’IP3 in IP4, abolisce l’entrata di Ca2+ e l’attivazione di NFAT. In accordo con tali dati in vitro, l’inibizione dell’ITPKB in vivo, previene l’attivazione di NFAT, riducendo pertanto la permeabilità vascolare, che dipende dall’attivazione di NFAT nelle DCs.
Diversamente dalle DCs, sebbene l’IP3R3 sia espresso a livello della PM dei macrofagi, presenta un minor livello di colocalizzazione con il CD14. Inoltre, in seguito ad una stimolazione con l’LPS, l’internalizzazione del CD14 avviene più rapidamente nei macrofagi rispetto a quanto avviene nelle DCs. Questi dati possono in parte spiegare il motivo della mancata attivazione della via di trasduzione del segnale di CD14/NFAT nei macrofagi in risposta all’LPS.
Complessivamente, questi dati indicano che il meccanismo di mobilizzazione del Ca2+ innescato dal CD14 richiede l’attivazione dell’ITPKB e la produzione dell’IP4 come secondo messaggero, il quale, in seguito, apre l’IP3R3 a livello della PM, inducendo un flusso monofasico di Ca2+ che porta all’attivazione della cascata di trasduzione del segnale di NFAT. Infine, questi dati suggeriscono che
l’ITPKB potrebbe essere presa in considerazione come nuovo bersaglio molecolare per terapie anti-infiammatorie volte a inibire funzioni specifiche delle DCs.Innate immune myeloid cells sense the presence of microbes or microbial products through pattern recognition receptors. Among these, Toll-like receptors (TLRs) are the best-characterized. Toll-like receptor 4 (TLR4), together with CD14 and MD-2, forms the multi-receptor complex for the Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria. CD14 concentrates the LPS signal and mediates the relocation of TLR4 and MD-2 to the endosome. After acute LPS exposure, CD14, independently of TLR4, activates the NFAT signalling pathway through src family kinase and PLCγ2 activation that leads to a rapid Ca2+ influx and Calcineurin activation. This function of CD14 is cell type specific, being active in dendritic cells (DCs) and not in macrophages. In the present work, we investigated the mechanism of CD14-mediated Ca2+ mobilization in DCs and we proposed an explanation for the lack of CD14/NFAT pathway activation in macrophages in response to LPS. We revealed that, both in mouse DCs and in a newly discovered human CD14+ DC subpopulation, IP3 receptor 3 (IP3R3) is expressed not only in the intracellular compartments such as endoplasmic reticulum (ER) but also at the plasma membrane (PM) and interestingly, it colocalizes with CD14 in lipid rafts. We found that, Ca2+ mobilization in LPS-stimulated DCs is due to a direct Ca2+ influx from the extracellular space, that relies on IP3R3 and requires IP4 rather than IP3 as second messenger. Indeed, the silencing of IP3R3 or the inhibition of ITPKB, the kinase implicated in the IP3 to IP4 conversion, abolishes Ca2+ entry and NFAT activation. Conforming to our in vitro results, the inhibition of ITPKB in vivo, prevents the activation of NFAT thus reducing vascular permeability, which depends on NFAT activation in DCs. Differently from DCs, although IP3R3 is expressed at the PM of macrophages it shows a low level of colocalization with CD14. Besides, upon LPS stimulation, CD14 internalization occurs more rapidly in macrophages compared to DCs. These reasons explain at least in part the absence of CD14/NFAT pathway activation in macrophages in response to LPS. Taken together, our results indicate that the mechanism of Ca2+ mobilization triggered by CD14 requires the activation of ITPKB and the production of IP4 as second messenger, which, in turn, opens IP3R3 at the PM inducing a monophasic Ca2+ influx that leads to the activation of the NFAT pathway. Finally, our data suggest that ITPKB could be considered as a new target for anti-inflammatory therapies aimed at inhibiting specific DC functions.
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Vautrin-Glabik, Alexia. "Implication du récepteur de l'inositol 1,4,5-trisphosphate de type 3 (IP3R3) dans les processus migratoires des cellules cancéreuses mammaires humaines." Thesis, Amiens, 2017. http://www.theses.fr/2017AMIE0039/document.
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Le cancer du sein est le cancer féminin le plus fréquent et le plus létal chez la femme dans le monde. Malgré l'amélioration du dépistage dans les phases précoces du développement tumoral, il demeure difficile de traiter les phases tardives lorsque les processus métastatiques sont engagés. Le développement métastatique dépend notamment de l'acquisition de capacités migratoires par les cellules épithéliales impliquant un remodelage du cytosquelette, hautement dépendant de la concentration calcique intracellulaire. Alors que les travaux se sont intéressés à l'implication des canaux ioniques membranaires dans les processus de migration, le rôle des récepteurs à l'inositol 1,4,5-trisphosphate (IP₃Rs) reste peu étudié et donc méconnu. Dans un premier temps nous avons montré une augmentation du niveau d'expression d'IP₃R3 avec le niveau du potentiel migratoire de trois lignées cancéreuses mammaires humaines : MCF-7 (les moins migrantes), MDA-MB-231 et MDA-MB-435s (les plus migrantes). D'autre part, nous montrons que la modulation de l'expression d'IP₃R3 module leurs capacités migratoires: elles sont diminuées par l'inhibition d'IP₃R3, alors qu'elles sont augmentées par la surexpression d'IP₃R3 dans les cellules mammaires peu migrantes. De plus, l'inhibition d'IP₃R3 révèle un signal calcique oscillant, alors que sa surexpression induit un signal calcique maintenu dans ces cellules. Dans un second temps, nous avons mis en évidence une corrélation inverse entre le niveau d'expression d'IP₃R3 et la morphologie arrondie de ces trois lignées cellulaires. En effet, plus la morphologie cellulaire est arrondie, plus l'expression d'IP₃R3 est importante. Par ailleurs, l'inhibition d'IP₃R3 induit un arrondissement des cellules migrantes et une diminution des protrusions membranaires accompagnés d’une diminution de leur adhésion. Ces résultats suggèrent fortement l'implication d'IP₃R3 dans la modulation des acteurs du cytosquelette. En effet, l'inhibition d'IP₃R3 induit une diminution de l'expression de l'ARHGAP18, de l'activité de RhoA et de l'expression de Cdc42. Ces Rho GTPases permettent à leur tour une diminution de la phosphorylation de FAK_⁸⁶¹ et la réorganisation du cytosquelette d'actine et de profiline. Enfin, dans un modèle migratoire, le profil oscillant s'établit dès réalisation d'une blessure et prédomine 3 h après dans les cellules du front de migration alors qu'il se met en place dans les cellules à l'arrière uniquement après 3 h. L'intervalle spatio-temporel de ce signal calcique oscillant reflète une dynamique calcique intracellulaire nécessaire aux processus migratoires et au remodelage du cytosquelette des cellules du cancer du sein. En conclusion, nos résultats révèlent un rôle clé de l'IP₃R3 dans les processus migratoires et dans le remodelage du cytosquelette de profilactine via la voie ARHGAP18/ RhoA/ FAK associé à une modulation du profil calcique intracellulaireBreast cancer is the most common lethal cancer in women in worldwide. In spite of screening improvement in early stages of tumor development, it remains difficult to cure late stages when metastases are begun. Metastatic development depends on migratory capacities acquisition by epithelial cells, involving a cytoskeleton remodeling, highly depending of intracellular calcium concentration. While plasma membrane calcium channels have been highly studied in migration processes, the role of IP₃Rs remains misunderstood. Firstly, we highlighted a correlation between IP₃R3 expression level and migratory potential of three human breast cancer cell lines with different migratory potential. Indeed, the more the migratory profile increases, the more is the expression of IP₃R3. Moreover, IP₃R3 expression modulation regulates their migratory capacities. The migratory capacities decreased when silencing IP₃R3, whereas they increased by overexpressing IP₃R3 in the low migratory breast cancer cell line (MCF-7). Furthermore, IP₃R3 silencing reveals an oscillating calcium profile, while its overexpression induces a sustained calcium profile. Secondly, we demonstrated a reverse correlation between IP₃R3 expression level and rounded shape of these three cell lines. Indeed, the longer the cell has an elongated morphology, the greater the IP₃R3 expression is important. Moreover, IP₃R3 silencing induced a rounded shape of migrating cells and decreased of protrusions and adhesion. Our results suggest IP₃R3 implication in modulation of cytoskeleton actors. Indeed, knockdown of IP₃R3 induced a decrease of ARHGAP18 and Cdc42 expression, RhoA and FAK_⁸⁶¹ activity, and a reorganization of profilactin cytoskeleton. Furthermore, in a migratory model, oscillating profile is revealed at wound realization and predominates 3 h amer in cells of the front wound whereas it sets up in cells of back only amer 3 h. The spatio-temporal gap of this oscillating calcium signal reflects an intracellular calcium dynamic essential to migratory processes and cytoskeleton remodelling in breast cancer. In conclusion, our results reveal a key role of IP₃R3 in migratory processes by profilactin cytoskeleton remodeling through ARHGAP18/ RhoA/ FAK pathway thanks to intracellular calcium profile modulation
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Criollo-Cespedes, Alfredo. "Regulation of autophagy by IP3R and IKK complex." Paris 11, 2009. http://www.theses.fr/2009PA11T099.
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Nougarede, Adrien. "Molecular basis of BCL2L10/Nrh oncogenic activity in breast cancer." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1192/document.
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L'apoptose, ou « mort cellulaire programmée », joue un rôle clé dans de nombreux processus biologiques. Les protéines de la famille Bcl-2, dont l'expression est souvent altérée dans les cellules tumorales, sont les principaux régulateurs de l'apoptose. Parmi cette famille, la fonction exacte du répresseur apoptotique Nrh, aussi appelé BCL2L10 ou Bcl-B, reste à ce jour mal comprise. Bien que son expression ne soit pas détectable dans la plupart des tissus sains, on retrouve des niveaux élevés de Nrh corrélés à un mauvais pronostique dans les cancers du sein et de la prostate. Nous avons mis au jour un nouveau mécanisme selon lequel Nrz, l'orthologue de Nrh chez le poisson zèbre, interagit avec le domaine de liaison du ligand IP3 du canal calcique IP3R1. Il s'est avéré que la régulation négative des flux calciques par Nrz est critique lors du développement embryonnaire du poisson zèbre. Grâce à ces nouvelles données, nous avons cherché à comprendre la fonction de Nrh chez l'Homme, dans un contexte pathologique. Nous avons montré que Nrh interagit via son domaine BH4 avec le domaine de liaison du ligand du récepteur IP3R1 humain pour réguler l'homéostasie calcique et la mort cellulaire. Cette interaction définit Nrh comme la seule protéine de la famille Bcl-2 à réguler négativement la mort cellulaire exclusivement au niveau du réticulum endoplasmique. Pour aller plus loin, nous avons montré que la dissociation du complexe Nrh/IP3Rs sensibilise des cellules tumorales mammaires à l'action d'agents chimiothérapeutiques. Pour finir, nos résultats apportent une explication moléculaire sur la contribution de Nrh dans la résistance aux thérapies anti-tumoralesApoptosis, also called “Programmed Cell Death”, plays a key role in many biological processes and pathologies. The B-cell lymphoma 2 (Bcl-2) proteins, whose expression is often altered in tumor cells, are the main regulators of apoptosis.Among this family, the actual physiological function of the human apoptosis inhibitor Nrh, also referred to as BCL2L10 or Bcl-B, remains elusive. Although in most healthy tissues the Nrh protein is nearly undetectable, clinical studies have shown that Nrh expression is correlated with poor prognosis in breast and prostate carcinomas. We have shed light on a novel mechanism by which Nrz, the zebrafish ortholog of Nrh, was found to interact with the Ligand Binding Domain (LBD) of the Inositol-1,4,5-triphosphate receptor (IP3R) type-I Ca2+ channel. Indeed, the regulation of IP3Rs-mediated Ca2+ signaling by Nrz was shown to be critical during zebrafish embryogenesis. We used the knowledge gained with the zebrafish model to investigate Nrh function in cancer. We showed that Nrh interacts with the LBD of IP3Rs via its BH4 (Bcl-2 Homology 4) domain, which is critical to regulate intracellular Ca2+ trafficking and cell death. Actually, this interaction seems to be unique among the Bcl-2 family, and sets Nrh as the only Bcl-2 homolog to negatively regulate apoptosis by acting exclusively at the Endoplasmic Reticulum. Furthermore, we showed that disruption of the Nrh/IP3Rs complex primes Nrh-dependent cells to apoptotic cell death and enhances chemotherapy efficiency in breast cancer cell lines.Lastly our results bring a new insight to the role of Nrh regarding chemotherapy resistance
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Criollo, Céspedes Alfredo. "Regulación de la autofagia por el receptor del inositol trisfosfato (IP3R)." Tesis, Universidad de Chile, 2009. http://repositorio.uchile.cl/handle/2250/105178.
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Doctor en BioquímicaLa macroautofagia, comúnmente referida como “autofagia” es la principal vía de degradación de proteínas, organelos y material citoplasmático, permitiendo de este modo el reciclaje del material intracelular. Este proceso consiste en el englobamiento de fracciones citosólicas por una estructura multimembranar llamada “autofagosoma”, el cual posteriormente se fusiona con el lisosoma para formar el “autofagolisosoma”. Luego el material comprendido en el autofagolisosoma es degradado por enzimas hidrolíticas. Un estudio mostró que la inhibición de la enzima inositolmonofosfatasa (IMPasa) usando litio y L690.330, inducía una disminución de los niveles basales del IP3 y en consecuencia la generación de autofagia. Nuestros resultados confirmaron estos datos previos, demostrando que el pre tratamiento con mio-inositol revierte la autofagia inducida por litio y L-690.330. Además se demuestra que el pre tratamiento con mio-inositol también revertía la autofagia inducida por privación de nutrientes. IP3 es ligando de su receptor de IP3 (IP3R), el cual es el principal canal de Ca2+ a nivel del retículo endoplásmico. El principal objetivo de esta tesis es evaluar el rol del IP3R en la regulación de la autofagia. Los resultados mostraron que la disminución de los niveles proteicos del IP3R usando siRNA específicos, así como el tratamiento con antagonistas químicos del IP3R, tales como xestosponginas B y C, estimulaban significativamente el aumento en los niveles de autofagia. Además, xestospongina B, así como también la privación de nutrientes, indujo una pérdida en la interacción entre Bcl-2 y Beclin-1, los cuales interactúan en condiciones basales. El tratamiento con xestospongina B no perturbó los niveles de Ca2+, tanto en retículo endoplásmico como en el citosol, concluyendo que la autofagia inducida por xestospongina B es independiente de una fluctuación del Ca2+. Los experimentos de inmunoprecipitación mostraron que Beclin-1 (regulador clave en la inducción de la autofagia) interactúa tanto con IP3R así como con Bcl-2 en condiciones basales, y la interacción de este complejo es atenuado bajo condiciones de privación de nutrientes o por tratamiento con ABT737, el cual es un mimetizador de dominios BH3. Este resultado sugiere la presencia de un complejo proteico en la regulación de la autofagia. El papel del retículo endoplásmico en el desarrollo de la autofagia toma gran significancia debido al reclutamiento de proteínas clave (IP3R, Beclin-1 and Bcl-2). La relación entre autofagia y estrés de retículo no es clara y por lo tanto se evaluó el efecto de agentes inductores de estrés de retículo en la inducción de la autofagia. Los resultados mostraron que tunicamicina, tapsigargina y brefeldina-A (agentes inductores de estrés de retículo) activaron el UPR (respuesta a proteínas mal plegadas) e indujeron autofagia. La disminución de los niveles de proteínas claves en el desarrollo de la autofagia (Atg5, Atg10, Atg12, Vps34 y Beclin-1) usando específicos RNAs interferentes atenuaron la autofagia inducida por agentes inductores de estrés de retículo y xestospongina B. Además, la sobreexpresión de Bcl-2 y Bcl-XL con destinación a retículo endoplásmico atenuó la autofagia inducida por xestospongina B e inhibidores de la IMPasa. Esta tesis muestra novedosos resultados, los cuales dan cuenta de un complejo proteico IP3R/Beclin-1/Bcl-2 en la regulación de la autofagia.
Macroautophagy (herein referred to as “autophagy”) is the major catabolic pathway for entire organelles, long-lived/ aberrant proteins and superfluous portions of the cytosol. It consists of the stepwise engulfment of substrate elements into distinctive multimembraned “autophagosomes”, which after fusion with lysosomes form singlemembraned autophagolysosomes. Into the autophagolysosome, the engulfed material is degradated by lisosomal hidrolytic enzymes, leading the recyclage of intracellular material. A study has suggested that myo-inositol-1,4,5-trisphosphate (IP3) could regulate autophagy because inhibition of inositol monophosphatase (IMPasa) by lithium or L-690.330 stimulates autophagy through the depletion of IP3. Our results have confirmed that the reduction of intracellular IP3 levels by IMPasa inhibitors (lithium and L.690.330) stimulates autophagy, whereas the enhancement of IP3 levels by pre treatment whit mio-inositol inhibits the lithium and L.690.330 effect. Moreover we have demostred that autophagy induced by nutrient privation was also inhibited by treatment with mio-inositol, but the effect of nutrient privation in the intracellular IP3 basal levels was not evaluated. IP3 acts on the IP3 receptor (IP3R), an IP3‑activated Ca2+ channel of the endoplasmic reticulum membrane and consequently we wanted to evaluate de roll of IP3R in the regulation of autophagy. The results obtained in this thesis show that knockdown of the IP3 receptor (IP3R) with specifics small interfering RNAs and pharmacological IP3R antagonist (xestospongin B and C) are a strong stimulus for the induction of autophagy, in addition, xestospongin B (like nutrient starvation) induced loss in the interaction between Beclin-1 and Bcl-2. Moreover, the autophagy promoted by xestospongin B not produced alterations in the steady-state Ca2+ levels in the ER or in the cytosol, therefore the autophagy induced by xestospongin B was Ca2+-independent. Immunoprecipitation assays shown that Beclin- 1 (key protein in the regulation of autophagy) interacts with IP3R and Bcl-2 in basal conditions, and this interaction may be attenuated both by nutrient starvation or ABT737 treatment, which is a mimetic compound of BH3. These results suggest the presence of a protein complex in the regulation of autophagy. The treatment whit ER stressors such as tunicamycin, thapsigargin and brepheldine A induced Unfolded Protein Responses (UPR) and autophagy. The autophagy induced by these agents showed to be IRE1α dependent, but the inhibition of autophagy showed an increase in the cell death, indicating a pro survival function of the autophagy upon endoplasmic reticumum stress conditions. The autophagy induced by treatment with xestospongin B and ER stressors was inhibited by knockdown of Atg5, Atg10, Atg12, Vps34 and Beclin-1, which are keys proteins in the autophagic process. We have also evaluated the roll of Bcl-2 and Bcl-XL in the inhibition of autophgy, and the results showed that Autophagy triggered by IMPasa inhibitors and xestospongin B was inhibited by Bcl-2 and Bcl-XL over expression specifically targeted to ER but not Bcl-2 or Bcl-XL proteins targeted to mitocondria. Altogether, these results suggest that IP3R form a regulator complex with Bcl-2 and Beclin-1, which exerts a major role in the physiological control of autophagy
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Ikebara, Juliane Midori. "Role of intracellular calcium receptor inositol 1,4,5-trisphosphate type 1 (IP3R1) in rat hippocampus after neonatal anoxia." reponame:Repositório Institucional da UFABC, 2016.
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Orientador: Prof. Dr. Alexandre Hiroaki KiharaDissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Neurociência e Cognição, 2016.
Anóxia é uma das maiores causas de morbidade e mortalidade neonatal, especialmente em neonatos pré-maturos, constituindo um importante problema de saúde pública devido às sequelas neurológicas permanentes em pacientes. A privação de oxigênio dispara uma série de cascatas, culminando em morte celular em regiões cerebrais mais vulneráveis, como o hipocampo. Neste processo de morte celular causada pela privação de oxigênio, o cálcio citosólico possui um papel crucial. Receptores intracelulares de inositol 1,4,5-trifosfato (IP3Rs) são importantes reguladores de níveis de deste cálcio, no entanto, não se sabe sobre sua função na anóxia. O objetivo deste estudo é analisar se os IP3Rs do tipo 1 (IP3R1) participam no processo de morte no hipocampo de ratos após a anóxia neonatal. A análise quantitativa de real-time PCR revelou uma diminuição da expressão gênica de IP3R1 24 horas após a anóxia neonatal. Na análise da distribuição de células IP3R1-positivas foi observada uma densidade de IP3R1 na região de CA1 em ambos os grupos, porém, não se observou diferença entre os grupos controle e anóxia. Interessantemente os animais anóxia apresentaram uma alta colocalização de IP3R1 e marcador de núcleo (DAPI), sugerindo que a anóxia causa uma translocação de IP3R1 para o núcleo nas células hipocampais. Além disso, o padrão de marcação mostrou diferentes tamanhos de clusters dos receptores, indicando uma organização diferente entre os grupos. Foi injetado 2-APB, um bloqueador de IP3R1, ou veículo, no hipocampo de forma bilateral após a anóxia. Foi utilizado metodologias de marcação de células degeneradas e foi visto que no grupo 2APB houve uma diminuição do número de células FJC-positivas e TUNEL-positivas em comparação ao grupo veículo anóxia. Porém, não foi observado nenhuma diferença de marcação entre os grupos na imunofluorescência de caspase-3 ativada. Não foi detectada nenhuma diferença entre os grupos no teste de labirinto de Barnes. No teste de campo aberto, observou-se que o grupo 2APB apresentam maiores níveis de ansiedade. Desta forma, este estudo pode contribuir com novas perspectivas na investigação de mecanismos de neurodegeneração ativadas pela privação de oxigênio.
Anoxia is one of the most prevalent causes of neonatal morbidity and mortality, especially in preterm neonates, constituting an important public health problem due to permanent neurological sequelae observed in patients. Oxygen deprivation triggers a series of simultaneous cascades, culminating in cell death mainly located in more vulnerable metabolic brain regions, such as the hippocampus. In the process of cell death by oxygen deprivation, cytosolic calcium plays crucial roles. Intracellular inositol 1,4,5-trisphosphate receptors (IP3Rs) are important regulators of cytosolic calcium levels, although the role of these receptors in neonatal anoxia is completely unknown. This study focused on the functional role of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in rat hippocampus after neonatal anoxia. Quantitative real-time PCR analysis revealed a decrease of IP3R1 gene expression 24 hours after neonatal anoxia. Distribution analysis of IP3R-positive cells was performed and we observed higher IP3R1 pixels quantity in CA1 of both groups; however, we were not able to observe alterations between control and anoxia animals. Interestingly, we observed that anoxia animals present a higher colocalization of IP3R1 and nucleus marker (DAPI), suggesting that neonatal anoxia may cause IP3R1 translocation to the nucleus in hippocampal cells. Furthermore, puncta-labelling pattern showed different cluster sizes, larger in control group, indicating different organization between groups. We injected 2-APB, an IP3R1 blocker, or vehicle in hippocampus bilaterally after anoxia. Labelling techniques of degenerate cells was performed and we observed that 2APB group decrease the number of FJC-positive cells compared to vehicle anoxia group. In contrast, TUNEL labelling and active caspase-3 immunofluorescence showed no difference between groups. Barnes maze test showed no differences between 2APB group and anoxia vehicle group. On the other hand, the open field test showed that 2APB group presents higher anxiety levels than vehicle group. In this way, this study may contribute to new perspectives in the investigation of neurodegenerative mechanisms triggered by oxygen deprivation.
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Ritaine, Abigaël. "On the mechanisms of regulation of the IP3R activity by its interaction with Bcl-2." Thesis, Lille, 2018. http://www.theses.fr/2018LIL1S101.
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L’homéostasie calcique est régulée par de nombreux canaux ioniques, parmi lesquels des canaux intracellulaires perméables au Ca2+, comme l’IP3R. Récemment, la protéine Bcl-2 a été montré comme régulant l’activité de ce canal ionique. Cependant, les acteurs moléculaires précis de cette interaction ne sont pas très bien établis. Ici nous montrons grâce à une nouvelle technique que l’IP3R est inhibé par le domaine BH4 de Bcl-2 et que ce domaine est nécessaire et suffisant pour inhiber son activité. De plus, la liaison de l’ABT-199 dans la poche hydrophobe de Bcl-2 conduit à un changement de structure du domaine BH4. Le niveau d’expression des différentes isoformes d’IP3R ainsi que des protéines Bcl-2 et Bcl-xL ont été étudié dans différentes lignées cancéreuses prostatiques. De manière intéressante, l’expression du récepteur à l’IP3 de type 3 (IP3R3) est augmentée en fonction de l’agressivité des lignées cancéreuses prostatiques. De plus, nous pouvons observer un effet important de l’IP3R3 sur la migration et l’invasion des lignées humaines de cancer de la prostate. Globalement, ces données montrent que l’IP3R3 participe à l’augmentation du potentiel métastatique des cellules cancéreuses prostatiques. Par conséquent, l’IP3R3 peut être un marqueur diagnostic intéressant ainsi qu’une cible thérapeutique, notamment pour les stades avancés de cancer de la prostateCalcium homeostasis is regulated by various ion channels, among which intracellular Ca2+-permeable channels, such as IP3R. Lately, Bcl-2 protein have been shown to regulate this ion channel activity. However, the study of the functional properties of IP3R in interaction with Bcl-2 is not a straightforward procedure and the molecular players implicated in that interaction are still not well established. Here, we show with the use of a new electrophysiological method, that the IP3R is inhibited by Bcl-2 via its BH4 domain and that the BH4 domain of Bcl-2 can inhibit by itself the single channel activity of the IP3R. Moreover, the binding of the ABT-199 in the hydrophobic groove of Bcl-2 leads to a tail-flip structural change in BH4 domain. We also studied the expression level of different IP3R isoforms as well as Bcl-2 and Bcl-xL protein in different prostate cancer cell lines. Interestingly, IP3R type 3 (IP3R3) expression is increased according the aggressiveness of prostate cancer cell lines. Indeed, IP3R3 was expressed preferentially in highly aggressive prostate cancer cell lines. Moreover, we can observe an significantly important effect of the IP3R3 on migration and invasion properties of human prostate cancer cell lines. Our study also revealed that IP3R3 was not involved in viability, proliferation. Overall, these data provide evidence on IP3R3 contribution to the increased metastatic potential of human prostate cancer cells. Therefore, IP3R3 could provide new perspective molecular target for the disease suppression, in particular at its advances stages
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Georgeon, Chartier Carole. "Evaluation des effets du vieillissement sur la signalisation calcique des cellules musculaires lisses des artères cérébrales dans les modèles murins C57BL6/J, SAMR1 et SAMP8 dans des conditions normales et sous restriction calorique." Thesis, Bordeaux 1, 2012. http://www.theses.fr/2012BOR14692/document.
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Au cours du vieillissement, les artères cérébrales subissent des modifications structurelles et fonctionnelles, notamment au niveau des cellules musculaires lisses (CML). La CML a pour rôle de maintenir la réactivité vasculaire via une signalisation calcique qui fait intervenir différents acteurs pouvant ainsi réguler deux phénomènes : la contraction et la relaxation. Ces acteurs rassemblent, au sein d’une même cellule, des canaux (CCVD, RYR, IP3R), des pompes calciques (SERCA, PMCA, NCX, STIM/ORAI) et leurs régulateurs (PLB, FKBP12.6, TRPP2, SARAF, TRIC). La restriction calorique (RC), apparaît comme étant un facteur retardant le vieillissement et ses pathologies. Notre travail s’est donc fortement impliqué dans l’étude de la signalisation calcique de la CML, en se focalisant sur les altérations génomiques et fonctionnelles au cours du vieillissement des artères cérébrales chez la souris C57Bl6/j. Nous avons ainsi pu mettre en évidence une altération de la signalisation calcique qui passe en partie par une modulation des niveaux d’expressions génique et protéique des canaux et pompes calciques impliqués dans ce phénomène, et par une modification fonctionnelle en termes de signaux calciques et de contraction. Après 5 mois de régime RC, il a été mis en évidence un ralentissement des altérations de la signalisation calcique liées au vieillissement et une diminution de l’oxydation des CMLDuring aging, cerebral arteries undergo structural and functional changes, particularly in smooth muscle cells (SMC). SMC is responsible for maintaining vascular reactivity via calcium signaling involving different actors and can regulate two phenomena: contraction and relaxation. These actors regroup channels (CCVD, RYR, IP3R) calcium pumps (SERCA, PMCA, NCX, STIM / ORAI) and their regulators (PLB, FKBP12.6, TRPP2, SARAF, TRIC). Caloric restriction (CR) appears as a factor in delaying aging and its pathologies. Our work is strongly involved in the study of calcium signaling in SMC, focusing on genomic and functional alterations during aging of cerebral arteries in mice C57BL6/J. We were able to demonstrate an altered calcium signaling, which is partly through modulation of gene and protein expression levels of calcium channels and pumps involved in this phenomenon, and a functional change in terms of calcium signals and contraction. After 5 months under RC, it was highlighted a slow calcium signaling alterations associated with aging and a decrease of SMC oxidation by SAMP8
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Mataragka, Stefania. "High-resolution optical analyses of IP3-evoked Ca2+ signals." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289124.
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Ca2+ is a universal intracellular messenger that regulates many cellular responses. Most cells express inositol 1,4,5-trisphosphate receptors (IP3R) that mediate Ca2+ release from the endoplasmic reticulum (ER) when they bind IP3 produced after activation of cell-surface receptors. Vertebrate genomes encode three closely related subtypes of IP3R (IP3R1-3). High-resolution optical analyses have revealed a hierarchy of IP3-evoked Ca2+ signals that are thought to arise from the co-regulation of IP3Rs by IP3 and Ca2+. The smallest events ('blips') report the opening of single IP3Rs, Ca2+ 'puffs' report the almost simultaneous opening of a few clustered IP3Rs, and as stimulus intensities increase further Ca2+ signals propagate regeneratively as Ca2+ waves. The aim of this study was to establish whether all three IP3R subtypes can generate Ca2+ puffs. I first used a haploid cell line (HAP1 cells) to generate, using CRISPR/Cas9, a line lacking all endogenous IP3Rs. However, for analyses of Ca2+ puffs, I used HEK cells that had been engineered, using CRISPR/Cas9 to disrupt endogenous genes, to express single IP3R subtypes. Local Ca2+ signals evoked by flash-photolysis of caged- IP3 were recorded using Cal520 and total internal reflection fluorescence (TIRF) microscopy in human embryonic kidney (HEK) cells. The Flika algorithm was used, and validated, for automated detection of Ca2+ puffs and to measure their properties. IP3 evoked Ca2+ puffs in wild-type HEK cells and in cells expressing single IP3R subtypes. In wild-type cells, the Ca2+ signals invariably propagated regeneratively to give global increases in cytosolic [Ca2+]. This occurred less frequently in cells expressing single IP3R subtypes, commensurate with their lower overall levels of IP3R expression. The properties of the Ca2+ puffs, including their rise and decay times, durations, the size of the unitary fluorescence steps as channels closed channel during the falling phase, and the estimated number of active IP3Rs in each Ca2+ puff, were broadly similar in each of the four cell lines. The latter observation suggests that despite lower overall levels of IP3R expression (~30%) in cells with single subtypes relative to WT cells, there is a mechanism that ensures formation of similarly sized IP3R clusters. The only significant differences between cell lines were the slower kinetics of the Ca2+ puffs evoked by IP3R2, which may suggest dissociation of IP3 from its receptor contributes to the termination of Ca2+ puffs. My results demonstrate, for the first time, that all three IP3R subtypes can generate Ca2+ puffs. I conclude that Ca2+ puffs are fundamental building blocks of all IP3-evoked Ca2+ signals.
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Usui, Ryota. "GPR40 activation initiates store-operated Ca²⁺ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells." Kyoto University, 2020. http://hdl.handle.net/2433/253196.
Full textBook chapters on the topic "IP3R3"
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Serysheva, Irina I., Mariah R. Baker, and Guizhen Fan. "Structural Insights into IP3R Function." In Advances in Experimental Medicine and Biology, 121–47. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-55858-5_6.
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Ritaine, Abigaël, George Shapovalov, and Natalia Prevarskaya. "Metabolic Disorders and Cancer: Store-Operated Ca2+ Entry in Cancer: Focus on IP3R-Mediated Ca2+ Release from Intracellular Stores and Its Role in Migration and Invasion." In Store-Operated Ca²⁺ Entry (SOCE) Pathways, 623–37. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-57732-6_31.
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Mak, Tak W., Josef Penninger, John Roder, Janet Rossant, and Mary Saunders. "IP3R1." In The Gene Knockout FactsBook, 630–31. Elsevier, 1998. http://dx.doi.org/10.1016/b978-012466044-1/50353-7.
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"Inositol Triphosphate Receptors (IP3Rs)." In Encyclopedia of Metalloproteins, 983. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-1533-6_100620.
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Zhang, Xiaoning, Rongzu Huang, Yang Zhou, Wenwen Zhou, and Xuhui Zeng. "IP3R Channels in Male Reproduction." In Prime Archives in Molecular Sciences. Vide Leaf, Hyderabad, 2021. http://dx.doi.org/10.37247/pacr.1.2020.17.
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Kevin Foskett, J., and Don-On Daniel Mak. "Regulation of IP3R Channel Gating by Ca2+ and Ca2+ Binding Proteins." In Current Topics in Membranes, 235–72. Elsevier, 2010. http://dx.doi.org/10.1016/s1063-5823(10)66011-5.
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Fajmut, Aleš. "Molecular Mechanisms and Targets of Cyclic Guanosine Monophosphate (cGMP) in Vascular Smooth Muscles." In Muscle Cell and Tissue - Novel Molecular Targets and Current Advances [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97708.
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Molecular mechanisms and targets of cyclic guanosine monophosphate (cGMP) accounting for vascular smooth muscles (VSM) contractility are reviewed. Mathematical models of five published mechanisms are presented, and four novel mechanisms are proposed. cGMP, which is primarily produced by the nitric oxide (NO) dependent soluble guanylate cyclase (sGC), activates cGMP-dependent protein kinase (PKG). The NO/cGMP/PKG signaling pathway targets are the mechanisms that regulate cytosolic calcium ([Ca2+]i) signaling and those implicated in the Ca2+-desensitization of the contractile apparatus. In addition to previous mathematical models of cGMP-mediated molecular mechanisms targeting [Ca2+]i regulation, such as large-conductance Ca2+-activated K+ channels (BKCa), Ca2+-dependent Cl− channels (ClCa), Na+/Ca2+ exchanger (NCX), Na+/K+/Cl− cotransport (NKCC), and Na+/K+-ATPase (NKA), other four novel mechanisms are proposed here based on the existing but perhaps overlooked experimental results. These are the effects of cGMP on the sarco−/endo- plasmic reticulum Ca2+-ATPase (SERCA), the plasma membrane Ca2+-ATPase (PMCA), the inositol 1,4,5-trisphosphate (IP3) receptor channels type 1 (IP3R1), and on the myosin light chain phosphatase (MLCP), which is implicated in the Ca2+-desensitization. Different modeling approaches are presented and discussed, and novel model descriptions are proposed.
Conference papers on the topic "IP3R3"
1
Avalle, L., A. Camporeale, G. Morciano, E. Ghetti, V. Orecchia, C. Giorgi, P. Pinton, and V. Poli. "PO-237 The pro-oncogenic transcription factor STAT3 regulates Ca2 +release and apoptosis from the endoplasmic reticulum via interaction with the Ca2 +CHANNEL IP3R3." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.270.
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SKUPIN, ALEXANDER, and MARTIN FALCKE. "THE ROLE OF IP3R CLUSTERING IN Ca2+ SIGNALING." In Proceedings of the 8th Annual International Workshop on Bioinformatics and Systems Biology (IBSB 2008). IMPERIAL COLLEGE PRESS, 2008. http://dx.doi.org/10.1142/9781848163003_0002.
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Son, Jeongin, Saie Mogre, and Adam Glick. "Abstract 2029: The ER stress protein IRE1a regulates intracellular calcium, ROS, and the UV damage response through the IP3R inhibitor CIB1." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-2029.
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Evasovic, J., C. Adajar, M. A. Hernandez, M. A. Ba, and C. A. Singer. "IL-17A Reduces the Proliferative Capacity of Asthmatic Airway Smooth Muscle Independent of TGF-Β1 Concentration via Altered ERK1/2 Signaling and Modulated miR-106b∼25-dependent IP3R1 and TGFΒR2 Expression." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a2850.
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