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1
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.
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Rahman, Taufiq. "Dynamic clustering of IP3 receptors by IP3." Biochemical Society Transactions 40, no. 2 (March 21, 2012): 325–30. http://dx.doi.org/10.1042/bst20110772.
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The versatility of Ca2+ as an intracellular messenger stems largely from the impressive, but complex, spatiotemporal organization of the Ca2+ signals. For example, the latter when initiated by IP3 (inositol 1,4,5-trisphosphate) in many cells manifest hierarchical recruitment of elementary Ca2+ release events (‘blips’ and then ‘puffs’) en route to global regenerative Ca2+ waves as the cellular IP3 concentration rises. The spacing of IP3Rs (IP3 receptors) and their regulation by Ca2+ are key determinants of these spatially organized Ca2+ signals, but neither is adequately understood. IP3Rs have been proposed to be pre-assembled into clusters, but their composition, geometry and whether clustering affects IP3R behaviour are unknown. Using patch-clamp recording from the outer nuclear envelope of DT40 cells expressing rat IP3R1 or IP3R3, we have recently shown that low concentrations of IP3 cause IP3Rs to aggregate rapidly and reversibly into small clusters of approximately four IP3Rs. At resting cytosolic Ca2+ concentrations, clustered IP3Rs open independently, but with lower open probability, shorter open duration and lesser IP3-sensitivity than lone IP3Rs. This inhibitory influence of clustering on IP3R is reversed when the [Ca2+]i (cytosolic free Ca2+ concentration) increases. The gating of clustered IP3Rs exposed to increased [Ca2+]i is coupled: they are more likely to open and close together, and their simultaneous openings are prolonged. Dynamic clustering of IP3Rs by IP3 thus exposes them to local Ca2+ rises and increases their propensity for a CICR (Ca2+-induced Ca2+ rise), thereby facilitating hierarchical recruitment of the elementary events that underlie all IP3-evoked Ca2+ signals.
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Bultynck, Geert, Daniela Rossi, Geert Callewaert, Ludwig Missiaen, Vincenzo Sorrentino, Jan B. Parys, and Humbert De Smedt. "The Conserved Sites for the FK506-binding Proteins in Ryanodine Receptors and Inositol 1,4,5-Trisphosphate Receptors Are Structurally and Functionally Different." Journal of Biological Chemistry 276, no. 50 (October 11, 2001): 47715–24. http://dx.doi.org/10.1074/jbc.m106573200.
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We compared the interaction of the FK506-binding protein (FKBP) with the type 3 ryanodine receptor (RyR3) and with the type 1 and type 3 inositol 1,4,5-trisphosphate receptor (IP3R1 and IP3R3), using a quantitative GST-FKBP12 and GST-FKBP12.6 affinity assay. We first characterized and mapped the interaction of the FKBPs with the RyR3. GST-FKBP12 as well as GST-FKBP12.6 were able to bind ∼30% of the solubilized RyR3. The interaction was completely abolished by FK506, strengthened by the addition of Mg2+, and weakened in the absence of Ca2+but was not affected by the addition of cyclic ADP-ribose. By using proteolytic mapping and site-directed mutagenesis, we pinpointed Val2322, located in the central modulatory domain of the RyR3, as a critical residue for the interaction of RyR3 with FKBPs. Substitution of Val2322for leucine (as in IP3R1) or isoleucine (as in RyR2) decreased the binding efficiency and shifted the selectivity to FKBP12.6; substitution of Val2322for aspartate completely abolished the FKBP interaction. Importantly, the occurrence of the valylprolyl residue as α-helix breaker was an important determinant of FKBP binding. This secondary structure is conserved among the different RyR isoforms but not in the IP3R isoforms. A chimeric RyR3/IP3R1, containing the core of the FKBP12-binding site of IP3R1 in the RyR3 context, retained this secondary structure and was able to interact with FKBPs. In contrast, IP3Rs did not interact with the FKBP isoforms. This indicates that the primary sequence in combination with the local structural environment plays an important role in targeting the FKBPs to the intracellular Ca2+-release channels. Structural differences in the FKBP-binding site of RyRs and IP3Rs may contribute to the occurrence of a stable interaction between RyR isoforms and FKBPs and to the absence of such interaction with IP3Rs.
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BULTYNCK, Geert, Karolina SZLUFCIK, Nael Nadif KASRI, Zerihun ASSEFA, Geert CALLEWAERT, Ludwig MISSIAEN, Jan B. PARYS, and Humbert DE SMEDT. "Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor type 1, but not type 3, via modulation of an isoform-specific Ca2+-dependent intramolecular interaction." Biochemical Journal 381, no. 1 (June 22, 2004): 87–96. http://dx.doi.org/10.1042/bj20040072.
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Thiol-reactive agents such as thimerosal have been shown to modulate the Ca2+-flux properties of IP3 (inositol 1,4,5-trisphosphate) receptor (IP3R) via an as yet unidentified mechanism [Parys, Missiaen, De Smedt, Droogmans and Casteels (1993) Pflügers Arch. 424, 516–522; Kaplin, Ferris, Voglmaier and Snyder (1994) J. Biol. Chem. 269, 28972–28978; Missiaen, Taylor and Berridge (1992) J. Physiol. (Cambridge, U.K.) 455, 623–640; Missiaen, Parys, Sienaert, Maes, Kunzelmann, Takahashi, Tanzawa and De Smedt (1998) J. Biol. Chem. 273, 8983–8986]. In the present study, we show that thimerosal potentiated IICR (IP3-induced Ca2+ release) and IP3-binding activity of IP3R1, expressed in triple IP3R-knockout R23-11 cells derived from DT40 chicken B lymphoma cells, but not of IP3R3 or [Δ1–225]-IP3R1, which lacks the N-terminal suppressor domain. Using a 45Ca2+-flux technique in permeabilized A7r5 smooth-muscle cells, we have shown that Ca2+ shifted the stimulatory effect of thimerosal on IICR to lower concentrations of thimerosal and thereby increased the extent of Ca2+ release. This suggests that Ca2+ and thimerosal synergetically regulate IP3R1. Glutathione S-transferase pull-down experiments elucidated an interaction between amino acids 1–225 (suppressor domain) and amino acids 226–604 (IP3-binding core) of IP3R1, and this interaction was strengthened by both Ca2+ and thimerosal. In contrast, calmodulin and sCaBP-1 (short Ca2+-binding protein-1), both having binding sites in the 1–225 region, weakened the interaction. This interaction was not found for IP3R3, in agreement with the lack of functional stimulation of this isoform by thimerosal. The interaction between the IP3-binding and transmembrane domains (amino acids 1–604 and 2170–2749 respectively) was not affected by thimerosal and Ca2+, but it was significantly inhibited by IP3 and adenophostin A. Our results demonstrate that thimerosal and Ca2+ induce isoform-specific conformational changes in the N-terminal part of IP3R1, leading to the formation of a highly IP3-sensitive Ca2+-release channel.
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VANLINGEN, Sara, Henk SIPMA, Patrick DE SMET, Geert CALLEWAERT, Ludwig MISSIAEN, Humbert DE SMEDT, and Jan B. PARYS. "Ca2+ and calmodulin differentially modulate myo-inositol 1,4,5-trisphosphate (IP3)-binding to the recombinant ligand-binding domains of the various IP3 receptor isoforms." Biochemical Journal 346, no. 2 (February 22, 2000): 275–80. http://dx.doi.org/10.1042/bj3460275.
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We have expressed the N-terminal 581 amino acids of type 1 myo-inositol 1,4,5-trisphosphate receptor (IP3R1), IP3R2 and IP3R3 as recombinant proteins [ligand-binding site 1 (lbs-1), lbs-2, lbs-3] in the soluble fraction of Escherichia coli. These recombinant proteins contain the complete IP3-binding domain and bound IP3 and adenophostin A with high affinity. Ca2+ and calmodulin were previously found to maximally inhibit IP3 binding to lbs-1 by 42±6 and 43±6% respectively, and with an IC50 of approx. 200 nM and 3 μM respectively [Sipma, De Smet, Sienaert, Vanlingen, Missiaen, Parys and De Smedt (1999) J. Biol. Chem. 274, 12157-12562]. We now report that Ca2+ inhibited IP3 binding to lbs-3 with an IC50 of approx. 700 nM (37±4% inhibition at 5 μM Ca2+), while IP3 binding to lbs-2 was not affected by increasing [Ca2+] from 100 nM to 25 μM. Calmodulin (10 μM) inhibited IP3 binding to lbs-3 by 37±4%, while IP3 binding to lbs-2 was inhibited by only 11±2%. The inhibition of IP3 binding to lbs-3 by calmodulin was dose-dependent (IC50≈ 2 μM). We conclude that the IP3-binding domains of the various IP3R isoforms differ in binding characteristics for IP3 and adenophostin A, and are differentially modulated by Ca2+ and calmodulin, suggesting that the various IP3R isoforms can have different intracellular functions.
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Pacher, Pál, Kumar Sharma, György Csordás, Yanqing Zhu, and György Hajnóczky. "Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-β." American Journal of Physiology-Renal Physiology 295, no. 5 (November 2008): F1303—F1312. http://dx.doi.org/10.1152/ajprenal.90343.2008.
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Transforming growth factor-β (TGF-β) has been implicated as a key factor in mediating many cellular processes germane to disease pathogenesis, including diabetic vascular complications. TGF-β alters cytosolic [Ca2+] ([Ca2+]c) signals, which in some cases may result from the downregulation of the IP3 receptor Ca2+ channels (IP3R). Ca2+ released by IP3Rs is effectively transferred from endoplasmic reticulum (ER) to the mitochondria to stimulate ATP production and to allow feedback control of the Ca2+ mobilization. To assess the effect of TGF-β on the ER-mitochondrial Ca2+ transfer, we first studied the [Ca2+]c and mitochondrial matrix Ca2+ ([Ca2+]m) signals in single preglomerular afferent arteriolar smooth muscle cells (PGASMC). TGF-β pretreatment (24 h) decreased both the [Ca2+]c and [Ca2+]m responses evoked by angiotensin II or endothelin. Strikingly, the [Ca2+]m signal was more depressed than the [Ca2+]c signal and was delayed. In permeabilized cells, TGF-β pretreatment attenuated the rate but not the magnitude of the IP3-induced [Ca2+]c rise, yet caused massive depression of the [Ca2+]m responses. ER Ca2+ storage and mitochondrial uptake of added Ca2+ were not affected by TGF-β. Also, TGF-β had no effect on mitochondrial distribution and on the ER-mitochondrial contacts assessed by two-photon NAD(P)H imaging and electron microscopy. Downregulation of both IP3R1 and IP3R3 was found in TGF-β-treated PGASMC. Thus, TGF-β causes uncoupling of mitochondria from the ER Ca2+ release. The sole source of this would be suppression of the IP3R-mediated Ca2+ efflux, indicating that the ER-mitochondrial Ca2+ transfer depends on the maximal rate of Ca2+ release. The impaired ER-mitochondrial coupling may contribute to the vascular pathophysiology associated with TGF-β production.
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Yuan, Zhaokan, Ting Cai, Jiang Tian, Alexander V. Ivanov, David R. Giovannucci, and Zijian Xie. "Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex." Molecular Biology of the Cell 16, no. 9 (September 2005): 4034–45. http://dx.doi.org/10.1091/mbc.e05-04-0295.
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We have shown that the caveolar Na/K-ATPase transmits ouabain signals via multiple signalplexes. To obtain the information on the composition of such complexes, we separated the Na/K-ATPase from the outer medulla of rat kidney into two different fractions by detergent treatment and density gradient centrifugation. Analysis of the light fraction indicated that both PLC-γ1 and IP3 receptors (isoforms 2 and 3, IP3R2 and IP3R3) were coenriched with the Na/K-ATPase, caveolin-1 and Src. GST pulldown assays revealed that the central loop of the Na/K-ATPase α1 subunit interacts with PLC-γ1, whereas the N-terminus binds IP3R2 and IP3R3, suggesting that the signaling Na/K-ATPase may tether PLC-γ1 and IP3 receptors together to form a Ca2+-regulatory complex. This notion is supported by the following findings. First, both PLC-γ1 and IP3R2 coimmunoprecipitated with the Na/K-ATPase and ouabain increased this interaction in a dose- and time-dependent manner in LLC-PK1 cells. Depletion of cholesterol abolished the effects of ouabain on this interaction. Second, ouabain induced phosphorylation of PLC-γ1 at Tyr783and activated PLC-γ1 in a Src-dependent manner, resulting in increased hydrolysis of PIP2. It also stimulated Src-dependent tyrosine phosphorylation of the IP3R2. Finally, ouabain induced Ca2+release from the intracellular stores via the activation of IP3 receptors in LLC-PK1 cells. This effect required the ouabain-induced activation of PLC-γ1. Inhibition of Src or depletion of cholesterol also abolished the effect of ouabain on intracellular Ca2+.
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Liu, Yi, Xiaopin Ma, Hisashi Fujioka, Jun Liu, Shengdi Chen, and Xiongwei Zhu. "DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1." Proceedings of the National Academy of Sciences 116, no. 50 (November 25, 2019): 25322–28. http://dx.doi.org/10.1073/pnas.1906565116.
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Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.
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Ren, Jun, Mingming Sun, Hao Zhou, Amir Ajoolabady, Yuan Zhou, Jun Tao, James R. Sowers, and Yingmei Zhang. "FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity." Science Advances 6, no. 38 (September 2020): eabc8561. http://dx.doi.org/10.1126/sciadv.abc8561.
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Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1−/− mice accentuated high-fat diet–induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid–induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.
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Sundivakkam, Premanand C., Angela M. Kwiatek, Tiffany T. Sharma, Richard D. Minshall, Asrar B. Malik, and Chinnaswamy Tiruppathi. "Caveolin-1 scaffold domain interacts with TRPC1 and IP3R3 to regulate Ca2+ store release-induced Ca2+ entry in endothelial cells." American Journal of Physiology-Cell Physiology 296, no. 3 (March 2009): C403—C413. http://dx.doi.org/10.1152/ajpcell.00470.2008.
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Caveolin-1 (Cav-1) regulates agonist-induced Ca2+ entry in endothelial cells; however, how Cav-1 regulates this process is poorly understood. Here, we describe that Cav-1 scaffold domain (NH2-terminal residues 82–101; CSD) interacts with transient receptor potential canonical channel 1 (TRPC1) and inositol 1,4,5-trisphosphate receptor 3 (IP3R3) to regulate Ca2+ entry. We have shown previously that the TRPC1 COOH-terminal residues 781-789 bind to CSD. In the present study, we show that the TRPC1 COOH-terminal residues 781-789 truncated (TRPC1-CΔ781-789) mutant expression abolished Ca2+ store release-induced Ca2+ influx in human dermal microvascular endothelial cell line (HMEC) and human embryonic kidney (HEK-293) cells. To understand the basis of loss of Ca2+ influx, we determined TRPC1 binding to IP3R3. We observed that the wild-type (WT)-TRPC1 but not TRPC1-CΔ781-789 effectively interacted with IP3R3. Similarly, WT-TRPC1 interacted with Cav-1, whereas TRPC1-CΔ781-789 binding to Cav-1 was markedly suppressed. We also assessed the direct binding of Cav-1 with TRPC1 and observed that the WT-Cav-1 but not the Cav-1ΔCSD effectively interacted with TRPC1. Since the interaction between TRPC1 and Cav-1ΔCSD was reduced, we measured Ca2+ store release-induced Ca2+ influx in Cav-1ΔCSD-transfected cells. Surprisingly, Cav-1ΔCSD expression showed a gain-of-function in Ca2+ entry in HMEC and HEK-293 cells. We observed a similar gain-of-function in Ca2+ entry when Cav-1ΔCSD was expressed in lung endothelial cells of Cav-1 knockout mice. Immunoprecipitation results revealed that WT-Cav-1 but not Cav-1ΔCSD interacted with IP3R3. Furthermore, we observed using confocal imaging the colocalization of IP3R3 with WT-Cav-1 but not with Cav-1ΔCSD on Ca2+ store release in endothelial cells. These findings suggest that CSD interacts with TRPC1 and IP3R3 and thereby regulates Ca2+ store release-induced Ca2+ entry in endothelial cells.
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Zhao, Guiling, Zachary P. Neeb, M. Dennis Leo, Judith Pachuau, Adebowale Adebiyi, Kunfu Ouyang, Ju Chen, and Jonathan H. Jaggar. "Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells." Journal of General Physiology 136, no. 3 (August 16, 2010): 283–91. http://dx.doi.org/10.1085/jgp.201010453.
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Plasma membrane large-conductance Ca2+-activated K+ (BKCa) channels and sarcoplasmic reticulum inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are expressed in a wide variety of cell types, including arterial smooth muscle cells. Here, we studied BKCa channel regulation by IP3 and IP3Rs in rat and mouse cerebral artery smooth muscle cells. IP3 activated BKCa channels both in intact cells and in excised inside-out membrane patches. IP3 caused concentration-dependent BKCa channel activation with an apparent dissociation constant (Kd) of ∼4 µM at physiological voltage (−40 mV) and intracellular Ca2+ concentration ([Ca2+]i; 10 µM). IP3 also caused a leftward-shift in BKCa channel apparent Ca2+ sensitivity and reduced the Kd for free [Ca2+]i from ∼20 to 12 µM, but did not alter the slope or maximal Po. BAPTA, a fast Ca2+ buffer, or an elevation in extracellular Ca2+ concentration did not alter IP3-induced BKCa channel activation. Heparin, an IP3R inhibitor, and a monoclonal type 1 IP3R (IP3R1) antibody blocked IP3-induced BKCa channel activation. Adenophostin A, an IP3R agonist, also activated BKCa channels. IP3 activated BKCa channels in inside-out patches from wild-type (IP3R1+/+) mouse arterial smooth muscle cells, but had no effect on BKCa channels of IP3R1-deficient (IP3R1−/−) mice. Immunofluorescence resonance energy transfer microscopy indicated that IP3R1 is located in close spatial proximity to BKCa α subunits. The IP3R1 monoclonal antibody coimmunoprecipitated IP3R1 and BKCa channel α and β1 subunits from cerebral arteries. In summary, data indicate that IP3R1 activation elevates BKCa channel apparent Ca2+ sensitivity through local molecular coupling in arterial smooth muscle cells.
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Wolfram, Francis, Edward Morris, and Colin W. Taylor. "Three-dimensional structure of recombinant type 1 inositol 1,4,5-trisphosphate receptor." Biochemical Journal 428, no. 3 (May 27, 2010): 483–89. http://dx.doi.org/10.1042/bj20100143.
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IP3Rs (inositol 1,4,5-trisphosphate receptors) are the intracellular channels that mediate release of Ca2+ from the endoplasmic reticulum in response to the many stimuli that evoke Ins(1,4,5)P3 formation. We characterized and purified type 1 IP3R heterologously expressed in Sf9 insect cells, and used the purified IP3R1 to determine its three-dimensional structure by electron microscopy and single-particle analysis. Recombinant IP3R1 has 4-fold symmetry with overall dimensions of approx. 19.5 nm×19.5 nm×17.5 nm. It comprises a small domain, which is likely to include the pore, linked by slender bridges to a large cytoplasmic domain with four petal-like regions. Our structures of recombinant IP3R1 and native cerebellar IP3R have similar appearances and dimensions. The only notable difference is the absence of a central stigma-like domain from the cytoplasmic region of recombinant IP3R1. The first structure of a recombinant IP3R is an important step towards developing three-dimensional structures of IP3R that better contribute to our understanding of the structural basis of IP3R activation.
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Zhao, Guiling, Adebowale Adebiyi, Eva Blaskova, Qi Xi, and Jonathan H. Jaggar. "Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca2+ signals, and vasoconstriction in cerebral arteries." American Journal of Physiology-Cell Physiology 295, no. 5 (November 2008): C1376—C1384. http://dx.doi.org/10.1152/ajpcell.00362.2008.
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Inositol 1,4,5-trisphosphate receptors (IP3Rs) regulate diverse physiological functions, including contraction and proliferation. There are three IP3R isoforms, but their functional significance in arterial smooth muscle cells is unclear. Here, we investigated relative expression and physiological functions of IP3R isoforms in cerebral artery smooth muscle cells. We show that 2-aminoethoxydiphenyl borate and xestospongin C, membrane-permeant IP3R blockers, reduced Ca2+ wave activation and global intracellular Ca2+ ([Ca2+]i) elevation stimulated by UTP, a phospholipase C-coupled purinergic receptor agonist. Quantitative PCR, Western blotting, and immunofluorescence indicated that all three IP3R isoforms were expressed in acutely isolated cerebral artery smooth muscle cells, with IP3R1 being the most abundant isoform at 82% of total IP3R message. IP3R1 knockdown with short hairpin RNA (shRNA) did not alter baseline Ca2+ wave frequency and global [Ca2+]i but abolished UTP-induced Ca2+ wave activation and reduced the UTP-induced global [Ca2+]i elevation by ∼61%. Antibodies targeting IP3R1 and IP3R1 knockdown reduced UTP-induced nonselective cation current ( Icat) activation. IP3R1 knockdown also reduced UTP-induced vasoconstriction in pressurized arteries with both intact and depleted sarcoplasmic reticulum (SR) Ca2+ by ∼45%. These data indicate that IP3R1 is the predominant IP3R isoform expressed in rat cerebral artery smooth muscle cells. IP3R1 stimulation contributes to UTP-induced Icat activation, Ca2+ wave generation, global [Ca2+]i elevation, and vasoconstriction. In addition, IP3R1 activation constricts cerebral arteries in the absence of SR Ca2+ release by stimulating plasma membrane Icat.
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Alzayady, Kamil J., and Richard J. H. Wojcikiewicz. "The role of Ca2+ in triggering inositol 1,4,5-trisphosphate receptor ubiquitination." Biochemical Journal 392, no. 3 (December 6, 2005): 601–6. http://dx.doi.org/10.1042/bj20050949.
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The IP3R (inositol 1,4,5-trisphosphate receptor) forms tetrameric Ca2+ channels in ER (endoplasmic reticulum) membranes, where channel activity is largely under the control of the co-agonists IP3 and Ca2+. In cells stimulated using extracellular ligands that persistently elevate phosphoinositidase C activity, IP3Rs are rapidly ubiquitinated and then degraded by the proteasome through as yet undefined mechanisms. Whereas binding of IP3 has been suggested to be a key event in the triggering of IP3R ubiquitination the role of Ca2+ in this process remains unknown. In the present study we use αT3-1 mouse pituitary cells expressing exogenous wild-type or mutant-type-I IP3Rs (IP3R1) to provide several lines of evidence that Ca2+ is also a trigger. Firstly, depletion of ER Ca2+ stores with thapsigargin blocked wild-type IP3R1 ubiquitination. Secondly, ubiquitination was blocked by mutating Glu2100 to Asp, which is known to markedly suppress Ca2+-binding to IP3R1 and the potency of Ca2+ as a stimulus for channel opening. Thirdly, mutating Asp2550 to Ala, which inhibits Ca2+ flux through the channel pore, partially inhibited ubiquitination indicating that Ca2+ released via wild-type IP3R1 contributes to triggering ubiquitination. Fourthly, and consistent with this conclusion, although suppression of increases in cytoplasmic Ca2+ concentration did not inhibit the ubiquitination of wild-type IP3R1, it strongly inhibited the ubiquitination of the Asp2550 to Ala mutant. Overall, these results show that Ca2+ plays an important role in triggering IP3R ubiquitination. Additional experiments with IP3R1 containing an Arg265 to Gln mutation, which decreases IP3-binding affinity, confirmed that IP3-binding also plays a role. Finally, the mutations at Glu2100, Asp2550 and Arg265 inhibited IP3R1 degradation to an extent that paralleled their inhibitory effects on ubiquitination. We conclude that IP3R ubiquitination and degradation are triggered by the concerted action of IP3- and Ca2+-binding.
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Yang, Yi-Dong, Man-Man Li, Gang Xu, Lan Feng, Er-Long Zhang, Jian Chen, De-Wei Chen, and Yu-Qi Gao. "Nogo-B Receptor Directs Mitochondria-Associated Membranes to Regulate Vascular Smooth Muscle Cell Proliferation." International Journal of Molecular Sciences 20, no. 9 (May 10, 2019): 2319. http://dx.doi.org/10.3390/ijms20092319.
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Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca2+(Ca2+m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP3R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca2+m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP3R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation, which contribute to the decrease of Ca2+m and mitochondrial impairment.
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Marongiu, Laura, Francesca Mingozzi, Clara Cigni, Roberta Marzi, Marco Di Gioia, Massimiliano Garrè, Dario Parazzoli, et al. "Inositol 1,4,5-trisphosphate 3-kinase B promotes Ca2+ mobilization and the inflammatory activity of dendritic cells." Science Signaling 14, no. 676 (March 30, 2021): eaaz2120. http://dx.doi.org/10.1126/scisignal.aaz2120.
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Innate immune responses to Gram-negative bacteria depend on the recognition of lipopolysaccharide (LPS) by a receptor complex that includes CD14 and TLR4. In dendritic cells (DCs), CD14 enhances the activation not only of TLR4 but also that of the NFAT family of transcription factors, which suppresses cell survival and promotes the production of inflammatory mediators. NFAT activation requires Ca2+ mobilization. In DCs, Ca2+ mobilization in response to LPS depends on phospholipase C γ2 (PLCγ2), which produces inositol 1,4,5-trisphosphate (IP3). Here, we showed that the IP3 receptor 3 (IP3R3) and ITPKB, a kinase that converts IP3 to inositol 1,3,4,5-tetrakisphosphate (IP4), were both necessary for Ca2+ mobilization and NFAT activation in mouse and human DCs. A pool of IP3R3 was located on the plasma membrane of DCs, where it colocalized with CD14 and ITPKB. Upon LPS binding to CD14, ITPKB was required for Ca2+ mobilization through plasma membrane–localized IP3R3 and for NFAT nuclear translocation. Pharmacological inhibition of ITPKB in mice reduced both LPS-induced tissue swelling and the severity of inflammatory arthritis to a similar extent as that induced by the inhibition of NFAT using nanoparticles that delivered an NFAT-inhibiting peptide specifically to phagocytic cells. Our results suggest that ITPKB may represent a promising target for anti-inflammatory therapies that aim to inhibit specific DC functions.
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Meng, Xue-Lian, Hui-Ling Zhang, Lin-Lin Feng, Man-Ling Chen, Ying-Ying Liu, Xia Yu, Feng-Ning Huan, et al. "Selenoprotein SelK increases the secretion of insulin from MIN6 β cells." RSC Advances 7, no. 56 (2017): 35038–47. http://dx.doi.org/10.1039/c7ra05379g.
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Yu, Ting, Yun Wang, Dong Qian, Xiaomeng Sun, Yurong Tang, Xiaoxue Shen, and Lin Lin. "Advanced Glycation End Products Impair Ca2+ Mobilization and Sensitization in Colonic Smooth Muscle Cells via the CAMP/PKA Pathway." Cellular Physiology and Biochemistry 43, no. 4 (2017): 1571–87. http://dx.doi.org/10.1159/000482005.
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Background/Aims: Excessive production of advanced glycation end products (AGEs) has been implicated in diabetes-related complications. This study aimed to investigate the mechanism by which AGEs potentially contribute to diabetes-associated colonic dysmotility. Methods: Control and streptozotocin (STZ)-induced diabetic groups were treated with aminoguanidine (AG). The colonic transit time and contractility of circular muscle strips was measured. ELISA, immunohistochemistry and western blotting were used to measure Nε-carboxymethyl-lysine (CML) levels. Primary cultured colonic smooth muscle cells (SMCs) were used in complementary in vitro studies. Results: Diabetic rats showed prolonged colonic transit time, weak contractility of colonic smooth muscle strips, and elevated levels of AGEs in the serum and colon tissues. cAMP levels, protein kinase-A (PKA) activities, and inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) phosphorylation were increased in the colon muscle tissues of diabetic rats, whereas RhoA/Rho kinase activity and myosin phosphatase target subunit 1 (MYPT1) phosphorylation were reduced. The inhibition of the production of AGEs (AG treatment) reduced these effects. In cultured colonic SMCs, AGE-BSA treatment increased IP3R3 phosphorylation and reduced intracellular Ca2+ concentration, myosin light chain (MLC) phosphorylation, RhoA/Rho kinase activity, and MYPT1 phosphorylation. The PKA inhibitor H-89 and anti-RAGE antibody inhibited the AGE-BSA–induced impairment of Ca2+ signaling and cAMP/PKA activation. Conclusion: AGEs/RAGE participate in diabetes-associated colonic dysmotility by interfering with Ca2+ signaling in colonic SMCs through targeting IP3R3-mediated Ca2+ mobilization and RhoA/Rho kinase-mediated Ca2+ sensitization via the cAMP/PKA pathway.
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Yamada, M., A. Miyawaki, K. Saito, T. Nakajima, M. Yamamoto-Hino, Y. Ryo, T. Furuichi, and K. Mikoshiba. "The calmodulin-binding domain in the mouse type 1 inositol 1,4,5-trisphosphate receptor." Biochemical Journal 308, no. 1 (May 15, 1995): 83–88. http://dx.doi.org/10.1042/bj3080083.
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We determined the amino acid sequence responsible for the calmodulin (CaM)-binding ability of mouse type 1 Ins(1,4,5)P3 receptor (IP3R1). We expressed various parts of IP3R1 from deleted cDNA and examined their CaM-binding ability. It was shown that the sequence stretching from Lys-1564 to Arg-1585 is necessary for the binding. The full-length IP3R1 with replacement of Trp-1576 by Ala lost its CaM-binding ability. Antibody against residues 1564-1585 of IP3R1 inhibited cerebellar IP3R1 from binding CaM. The fluorescence spectrum of the peptide that corresponds to residues 1564-1585 shifted when Ca(2+)-CaM was added. From the change in the fluorescence spectrum, we estimated the dissociation constant (KD) between the peptide and CaM to be 0.7 microM. The submicromolar value of KD suggests an actual interaction between CaM and IP3R1 within cells. The CaM-binding ability of other types of IP3Rs was also examined. A part of the type 2IP3R, including the region showing sequence identity with the CaM-binding domain of IP3R1, also bound CaM, while the expressed full-length type 3 IP3R did not.
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Marks, A. R. "Intracellular calcium-release channels: regulators of cell life and death." American Journal of Physiology-Heart and Circulatory Physiology 272, no. 2 (February 1, 1997): H597—H605. http://dx.doi.org/10.1152/ajpheart.1997.272.2.h597.
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Intracellular Ca2+-release channels on the sarcoplasmic reticulum of striated muscle [ryanodine receptors (RyRs)] and on the endoplasmic reticulum of almost all types of cells [inositol 1,4,5-trisphosphate receptors (IP3Rs)] comprise a unique family of molecules that are structurally and functionally distinct from all other known ion channels. These channels play crucial roles in Ca2+-mediated signaling that triggers excitation-contraction coupling, T-lymphocyte activation, fertilization, and many other cellular functions. Three forms of RyR have been identified: RyR1, expressed predominantly in skeletal muscle; RyR2, expressed predominantly in cardiac muscle; and RyR3, expressed in specialized muscles and nonmuscle tissues including the brain. RyR channels are tetramers composed of four subunits each with a molecular mass of approximately 560,000 Da. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein known as the FK506 binding protein (FKBP). FKBP is the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin that inhibit the prolyl isomerase activity of FKBP and can dissociate FKBP from RyRs. Rapamycin and FK506 increase the sensitivity of RyRs to agonists such as caffeine and could be a cause of cardiac dysfunction associated with high-dose immunosuppressant therapy by promoting leakage of Ca2+ from the sarcoplasmic reticulum. The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP. Three forms of IP3Rs (types 1, 2 and 3) have been characterized by cDNA cloning. Most cells have at least one form of IP3R, and many express all three types. Like RyRs, the IP3R channels are tetramers composed of four subunits (approximately 300,000 Da each). IP3R1 function is regulated by at least two major cellular signaling pathways: the second messenger IP3 activates the channel, and phosphorylation by nonreceptor protein tyrosine kinases (e.g., Fyn) increase its open probability. During end-stage human heart failure, RyR2 mRNA and protein are downregulated, whereas IP3R1 is upregulated, suggesting that altered Ca2+-release channel levels may contribute to defects in Ca2+ homeostasis. Cells that are deficient in IP3R1 exhibit defective T cell-receptor signaling and thus cannot be activated by T cell-receptor stimulation. IP3R1-deficient cells are also resistant to induced apoptosis. Thus RyRs and IP3Rs play critical roles in fundamental and diverse signaling phenomena that include excitation-contraction coupling, T-cell activation, and programmed cell death.
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Bononi, Angela, Carlotta Giorgi, Simone Patergnani, David Larson, Kaitlyn Verbruggen, Mika Tanji, Laura Pellegrini, et al. "BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation." Nature 546, no. 7659 (June 2017): 549–53. http://dx.doi.org/10.1038/nature22798.
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Liao, Chengheng, and Qing Zhang. "BBOX1 promotes triple-negative breast cancer progression by controlling IP3R3 stability." Molecular & Cellular Oncology 7, no. 6 (September 6, 2020): 1813526. http://dx.doi.org/10.1080/23723556.2020.1813526.
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Sun, Yi, Ana M. Rossi, Taufiq Rahman, and Colin W. Taylor. "Activation of IP3 receptors requires an endogenous 1-8-14 calmodulin-binding motif." Biochemical Journal 449, no. 1 (December 7, 2012): 39–49. http://dx.doi.org/10.1042/bj20121034.
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Binding of IP3 (inositol 1,4,5-trisphosphate) to the IP3-binding core (residues 224–604) of IP3Rs (IP3 receptors) initiates opening of these ubiquitous intracellular Ca2+ channels. The mechanisms are unresolved, but require conformational changes to pass through the suppressor domain (residues 1–223). A calmodulin-binding peptide derived from myosin light chain kinase uncouples these events. We identified a similar conserved 1-8-14 calmodulin-binding motif within the suppressor domain of IP3R1 and, using peptides and mutagenesis, we demonstrate that it is essential for IP3R activation, whether assessed by IP3-evoked Ca2+ release or patch-clamp recoding of nuclear IP3R. Mimetic peptides specifically inhibit activation of IP3R by uncoupling the IP3-binding core from the suppressor domain. Mutations of key hydrophobic residues within the endogenous 1-8-14 motif mimic the peptides. Our results show that an endogenous 1-8-14 motif mediates conformational changes that are essential for IP3R activation. The inhibitory effects of calmodulin and related proteins may result from disruption of this essential interaction.
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Ladenburger, Eva-Maria, Ivonne M. Sehring, Iris Korn, and Helmut Plattner. "Novel Types of Ca2+ Release Channels Participate in the Secretory Cycle of Paramecium Cells." Molecular and Cellular Biology 29, no. 13 (April 20, 2009): 3605–22. http://dx.doi.org/10.1128/mcb.01592-08.
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ABSTRACT A database search of the Paramecium genome reveals 34 genes related to Ca2+-release channels of the inositol-1,4,5-trisphosphate (IP3) or ryanodine receptor type (IP3R, RyR). Phylogenetic analyses show that these Ca2+ release channels (CRCs) can be subdivided into six groups (Paramecium tetraurelia CRC-I to CRC-VI), each one with features in part reminiscent of IP3Rs and RyRs. We characterize here the P. tetraurelia CRC-IV-1 gene family, whose relationship to IP3Rs and RyRs is restricted to their C-terminal channel domain. CRC-IV-1 channels localize to cortical Ca2+ stores (alveolar sacs) and also to the endoplasmic reticulum. This is in contrast to a recently described true IP3 channel, a group II member (P. tetraurelia IP3RN-1), found associated with the contractile vacuole system. Silencing of either one of these CRCs results in reduced exocytosis of dense core vesicles (trichocysts), although for different reasons. Knockdown of P. tetraurelia IP3RN affects trichocyst biogenesis, while CRC-IV-1 channels are involved in signal transduction since silenced cells show an impaired release of Ca2+ from cortical stores in response to exocytotic stimuli. Our discovery of a range of CRCs in Paramecium indicates that protozoans already have evolved multiple ways for the use of Ca2+ as signaling molecule.
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Tao, Rong, Chu-Pak Lau, and Gui-Rong Li. "Inositol 1,4,5-Trisphosphate Receptors Mediating Spontaneous Ca2+ Oscillation Favors Proliferation in Human Mesenchymal Stem Cells from Bone Marrow." Blood 108, no. 11 (November 16, 2006): 2572. http://dx.doi.org/10.1182/blood.v108.11.2572.2572.
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Abstract Although human mesenchymal stem cells (hMSCs) constitute a very small population of cells in bone marrow, they play an important role in the regulation of hematopoietic microenvironment. The self-renew and/or proliferation of hMSCs is believed to be particularly important in maintaining bone marrow niche; however, the regulation of this process is not fully understood. The present study was designed to investigate whether spontaneous Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate (IP3) receptors participates in the proliferation regulation in cultured hMSCs from bone marrow using RT-PCR, cell proliferation assay, Western-blotting analysis. It was found that no gene expression for ryanodine-sensitive receptors was detected in undifferentiated hMSCs, while three subtypes of IP3 receptor genes (i.e. IP3R1, IP3R2, and IP3R3), and genes for sarco/endoplasmic reticulum Ca2+ ATPases (SERCA) (ATP2A1, ATP2A2, and ATP2A3) were expressed in these cells. The proliferation of hMSCs was reduced by inhibiting Ca2+ oscillation with the IP3 receptor antagonist 2-aminoethyl diphenylborinate (2-APB) or the SERCA inhibitor cyclopiazonic acid (CPA). In addition, inhibition of Mek/Erk and PI-3K/Akt signaling also decreased hMSCs proliferation. The relation of Ca2+ oscillation to the activity of these kinases was revealed by Western blotting analysis. Erk1/2 (Thr185/Tyr187) phosphorylation level was found to be reduced by directly inhibiting Ca2+ oscillation with 2-APB or CPA either in the presence or absence of serum. However, Akt (Thr308) phosphorylation was decreased only in the presence of serum, and serum-free starvation (2 h) eliminated Akt (Thr308) phosphorylation. Finally the calmodulin inhibitors W-7 and SKF-7171A were employed to further investigate whether this ubiquitous Ca2+ sensor is involved in the Ca2+ signal-mediated effect. Similarly, the phosphorylation level of Erk1/2 (Thr185/Tyr187) and Akt (Thr308) reduced upon the inhibition of calmodulin. In conclusion, our results demonstrate that IP3 receptors-mediated spontaneous Ca2+ oscillation and/or Ca2+/calmodulin signaling play(s) a crucial role in the regulation of cell proliferation mediated by multiple pro-proliferation signaling pathways (e.g. Mek/Erk and PI-3K/Akt). Importantly, Erk1/2 phosphorylation is sensitive to spontaneous Ca2+ oscillation, and therefore is responsible for the proliferation induced by Ca2+ oscillation in hMSCs.
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Kuchay, Shafi, Carlotta Giorgi, Daniele Simoneschi, Julia Pagan, Sonia Missiroli, Anita Saraf, Laurence Florens, et al. "PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth." Nature 546, no. 7659 (June 2017): 554–58. http://dx.doi.org/10.1038/nature22965.
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Filadi, Riccardo, Nuno Santos Leal, Bernadette Schreiner, Alice Rossi, Giacomo Dentoni, Catarina Moreira Pinho, Birgitta Wiehager, et al. "TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+ Transfer." Current Biology 28, no. 3 (February 2018): 369–82. http://dx.doi.org/10.1016/j.cub.2017.12.047.
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Rosa, Nicolas, Hristina Ivanova, Larry E. Wagner, Justin Kale, Rita La Rovere, Kirsten Welkenhuyzen, Nikolaos Louros, et al. "Bcl-xL acts as an inhibitor of IP3R channels, thereby antagonizing Ca2+-driven apoptosis." Cell Death & Differentiation 29, no. 4 (November 8, 2021): 788–805. http://dx.doi.org/10.1038/s41418-021-00894-w.
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AbstractAnti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca2+ dynamics by controlling IP3 receptor (IP3R) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IP3Rs and preventing pro-apoptotic Ca2+ release and Bcl-xL sensitizing IP3Rs to low [IP3] and promoting pro-survival Ca2+ oscillations. We here demonstrate that Bcl-xL too inhibits IP3R-mediated Ca2+ release by interacting with the same IP3R regions as Bcl-2. Via in silico superposition, we previously found that the residue K87 of Bcl-xL spatially resembled K17 of Bcl-2, a residue critical for Bcl-2’s IP3R-inhibitory properties. Mutagenesis of K87 in Bcl-xL impaired its binding to IP3R and abrogated Bcl-xL’s inhibitory effect on IP3Rs. Single-channel recordings demonstrate that purified Bcl-xL, but not Bcl-xLK87D, suppressed IP3R single-channel openings stimulated by sub-maximal and threshold [IP3]. Moreover, we demonstrate that Bcl-xL-mediated inhibition of IP3Rs contributes to its anti-apoptotic properties against Ca2+-driven apoptosis. Staurosporine (STS) elicits long-lasting Ca2+ elevations in wild-type but not in IP3R-knockout HeLa cells, sensitizing the former to STS treatment. Overexpression of Bcl-xL in wild-type HeLa cells suppressed STS-induced Ca2+ signals and cell death, while Bcl-xLK87D was much less effective in doing so. In the absence of IP3Rs, Bcl-xL and Bcl-xLK87D were equally effective in suppressing STS-induced cell death. Finally, we demonstrate that endogenous Bcl-xL also suppress IP3R activity in MDA-MB-231 breast cancer cells, whereby Bcl-xL knockdown augmented IP3R-mediated Ca2+ release and increased the sensitivity towards STS, without altering the ER Ca2+ content. Hence, this study challenges the current paradigm of divergent functions for Bcl-2 and Bcl-xL in Ca2+-signaling modulation and reveals that, similarly to Bcl-2, Bcl-xL inhibits IP3R-mediated Ca2+ release and IP3R-driven cell death. Our work further underpins that IP3R inhibition is an integral part of Bcl-xL’s anti-apoptotic function.
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HIROTA, Junji, Hideaki ANDO, Kozo HAMADA, and Katsuhiko MIKOSHIBA. "Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1." Biochemical Journal 372, no. 2 (June 1, 2003): 435–41. http://dx.doi.org/10.1042/bj20030110.
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The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is an intracellular IP3-gated Ca2+ channel that is located on intracellular Ca2+ stores and modulates Ca2+ signalling. Using the yeast two-hybrid system, we screened a mouse brain cDNA library with bait constructs for mouse IP3R type 1 (IP3R1) to identify IP3R1-associated proteins. In this way, we found that carbonic anhydrase-related protein (CARP) is a novel IP3R1-binding protein. Western blot analysis revealed that CARP is expressed exclusively in Purkinje cells of the cerebellum, in which IP3R1 is abundantly expressed. Immunohistochemical analysis showed that the subcellular localization of CARP in Purkinje cells is coincident with that of IP3R1. Biochemical analysis also showed that CARP is co-precipitated with IP3R1. Using deletion mutagenesis, we established that amino acids 45–291 of CARP are essential for its association with IP3R1, and that the CARP-binding site is located within the modulatory domain of IP3R1 amino acids 1387–1647. CARP inhibits IP3 binding to IP3R1 by reducing the affinity of the receptor for IP3. As reported previously, sensitivity to IP3 for IP3-induced Ca2+ release in Purkinje cells is low compared with that in other tissues. This could be due to co-expression of CARP with IP3R in Purkinje cells and its inhibitory effects on IP3 binding.
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Azumaya, Caleigh M., Emily A. Linton, Caitlin J. Risener, Terunaga Nakagawa, and Erkan Karakas. "Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist." Journal of Biological Chemistry 295, no. 6 (January 8, 2020): 1743–53. http://dx.doi.org/10.1074/jbc.ra119.011570.
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Calcium-mediated signaling through inositol 1,4,5-triphosphate receptors (IP3Rs) is essential for the regulation of numerous physiological processes, including fertilization, muscle contraction, apoptosis, secretion, and synaptic plasticity. Deregulation of IP3Rs leads to pathological calcium signaling and is implicated in many common diseases, including cancer and neurodegenerative, autoimmune, and metabolic diseases. Revealing the mechanism of activation and inhibition of this ion channel will be critical to an improved understanding of the biological processes that are controlled by IP3Rs. Here, we report structural findings of the human type-3 IP3R (IP3R-3) obtained by cryo-EM (at an overall resolution of 3.8 Å), revealing an unanticipated regulatory mechanism where a loop distantly located in the primary sequence occupies the IP3-binding site and competitively inhibits IP3 binding. We propose that this inhibitory mechanism must differ qualitatively among IP3R subtypes because of their diverse loop sequences, potentially serving as a key molecular determinant of subtype-specific calcium signaling in IP3Rs. In summary, our structural characterization of human IP3R-3 provides critical insights into the mechanistic function of IP3Rs and into subtype-specific regulation of these important calcium-regulatory channels.
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Vervliet, Tim, Jan B. Parys, and Geert Bultynck. "Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites: the complexity of protein–protein interactions for channel regulation." Biochemical Society Transactions 43, no. 3 (June 1, 2015): 396–404. http://dx.doi.org/10.1042/bst20140298.
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The 12- and 12.6-kDa FK506-binding proteins, FKBP12 (12-kDa FK506-binding protein) and FKBP12.6 (12.6-kDa FK506-binding protein), have been implicated in the binding to and the regulation of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs), both tetrameric intracellular Ca2+-release channels. Whereas the amino acid sequences responsible for FKBP12 binding to RyRs are conserved in IP3Rs, FKBP12 binding to IP3Rs has been questioned and could not be observed in various experimental models. Nevertheless, conservation of these residues in the different IP3R isoforms and during evolution suggested that they could harbour an important regulatory site critical for IP3R-channel function. Recently, it has become clear that in IP3Rs, this site was targeted by B-cell lymphoma 2 (Bcl-2) via its Bcl-2 homology (BH)4 domain, thereby dampening IP3R-mediated Ca2+ flux and preventing pro-apoptotic Ca2+ signalling. Furthermore, vice versa, the presence of the corresponding site in RyRs implied that Bcl-2 proteins could associate with and regulate RyR channels. Recently, the existence of endogenous RyR–Bcl-2 complexes has been identified in primary hippocampal neurons. Like for IP3Rs, binding of Bcl-2 to RyRs also involved its BH4 domain and suppressed RyR-mediated Ca2+ release. We therefore propose that the originally identified FKBP12-binding site in IP3Rs is a region critical for controlling IP3R-mediated Ca2+ flux by recruiting Bcl-2 rather than FKBP12. Although we hypothesize that anti-apoptotic Bcl-2 proteins, but not FKBP12, are the main physiological inhibitors of IP3Rs, we cannot exclude that Bcl-2 could help engaging FKBP12 (or other FKBP isoforms) to the IP3R, potentially via calcineurin.
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Jia, Cuihong, and Colleen C. Hegg. "Effect of IP3R3 and NPY on age-related declines in olfactory stem cell proliferation." Neurobiology of Aging 36, no. 2 (February 2015): 1045–56. http://dx.doi.org/10.1016/j.neurobiolaging.2014.11.007.
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Kuchay, Shafi, Mohsan Saeed, Carlotta Giorgi, Jie Li, Hans-Heinrich Hoffmann, Paolo Pinton, Charles M. Rice, and Michele Pagano. "NS5A Promotes Constitutive Degradation of IP3R3 to Counteract Apoptosis Induced by Hepatitis C Virus." Cell Reports 25, no. 4 (October 2018): 833–40. http://dx.doi.org/10.1016/j.celrep.2018.09.088.
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Ye, Risheng, Min Ni, Miao Wang, Shengzhan Luo, Genyuan Zhu, Robert H. Chow, and Amy S. Lee. "Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes." Journal of Endocrinology 210, no. 2 (May 12, 2011): 209–17. http://dx.doi.org/10.1530/joe-11-0012.
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The inositol 1,4,5-trisphosphate receptors (IP3Rs) as ligand-gated Ca2+ channels are key modulators of cellular processes. Despite advances in understanding their critical role in regulating neuronal function and cell death, how this family of proteins impact cell metabolism is just emerging. Unexpectedly, a transgenic mouse line (D2D) exhibited progressive glucose intolerance as a result of transgene insertion. Inverse PCR was used to identify the gene disruption in the D2D mice. This led to the discovery that Itpr1 is among the ten loci disrupted in chromosome 6. Itpr1 encodes for IP3R1, the most abundant IP3R isoform in mouse brain and also highly expressed in pancreatic β-cells. To study IP3R1 function in glucose metabolism, we used the Itpr1 heterozygous mutant mice, opt/+. Glucose homeostasis in male mice cohorts was examined by multiple approaches of metabolic phenotyping. Under regular diet, the opt/+ mice developed glucose intolerance but no insulin resistance. Decrease in second-phase glucose-stimulated blood insulin level was observed in opt/+ mice, accompanied by reduced β-cell mass and insulin content. Strikingly, when fed with high-fat diet, the opt/+ mice were more susceptible to the development of hyperglycemia, glucose intolerance, and insulin resistance. Collectively, our studies identify the gene Itpr1 being interrupted in the D2D mice and uncover a novel role of IP3R1 in regulation of in vivo glucose homeostasis and development of diet-induced diabetes.
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Zhang, Dan, Michael J. Boulware, Matthew R. Pendleton, Taisaku Nogi, and Jonathan S. Marchant. "The inositol 1,4,5-trisphosphate receptor (Itpr) gene family in Xenopus: identification of type 2 and type 3 inositol 1,4,5-trisphosphate receptor subtypes." Biochemical Journal 404, no. 3 (May 29, 2007): 383–91. http://dx.doi.org/10.1042/bj20070101.
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Studies in the Xenopus model system have provided considerable insight into the developmental role of intracellular Ca2+ signals produced by activation of IP3Rs (inositol 1,4,5-trisphosphate receptors). However, unlike mammalian systems where three IP3R subtypes have been well characterized, our molecular understanding of the IP3Rs that underpin Ca2+ signalling during Xenopus embryogenesis relate solely to the original characterization of the ‘Xenopus IP3R’ cloned and purified from Xenopus laevis oocytes several years ago. In the present study, we have identified Xenopus type 2 and type 3 IP3Rs and report the full-length sequence, genomic architecture and developmental expression profile of these additional IP3R subtypes. In the light of the emerging genomic resources and opportunities for genetic manipulation in the diploid frog Xenopus tropicalis, these data will facilitate manipulations to resolve the contribution of IP3R diversity in Ca2+ signalling events observed during vertebrate development.
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Tovey, Stephen C., Skarlatos G. Dedos, Emily J. A. Taylor, Jarrod E. Church, and Colin W. Taylor. "Selective coupling of type 6 adenylyl cyclase with type 2 IP3 receptors mediates direct sensitization of IP3 receptors by cAMP." Journal of Cell Biology 183, no. 2 (October 20, 2008): 297–311. http://dx.doi.org/10.1083/jcb.200803172.
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Interactions between cyclic adenosine monophosphate (cAMP) and Ca2+ are widespread, and for both intracellular messengers, their spatial organization is important. Parathyroid hormone (PTH) stimulates formation of cAMP and sensitizes inositol 1,4,5-trisphosphate receptors (IP3R) to IP3. We show that PTH communicates with IP3R via “cAMP junctions” that allow local delivery of a supramaximal concentration of cAMP to IP3R, directly increasing their sensitivity to IP3. These junctions are robust binary switches that are digitally recruited by increasing concentrations of PTH. Human embryonic kidney cells express several isoforms of adenylyl cyclase (AC) and IP3R, but IP3R2 and AC6 are specifically associated, and inhibition of AC6 or IP3R2 expression by small interfering RNA selectively attenuates potentiation of Ca2+ signals by PTH. We define two modes of cAMP signaling: binary, where cAMP passes directly from AC6 to IP3R2; and analogue, where local gradients of cAMP concentration regulate cAMP effectors more remote from AC. Binary signaling requires localized delivery of cAMP, whereas analogue signaling is more dependent on localized cAMP degradation.
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Narayanan, Damodaran, Adebowale Adebiyi, and Jonathan H. Jaggar. "Inositol trisphosphate receptors in smooth muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 11 (June 1, 2012): H2190—H2210. http://dx.doi.org/10.1152/ajpheart.01146.2011.
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Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of tetrameric intracellular calcium (Ca2+) release channels that are located on the sarcoplasmic reticulum (SR) membrane of virtually all mammalian cell types, including smooth muscle cells (SMC). Here, we have reviewed literature investigating IP3R expression, cellular localization, tissue distribution, activity regulation, communication with ion channels and organelles, generation of Ca2+ signals, modulation of physiological functions, and alterations in pathologies in SMCs. Three IP3R isoforms have been identified, with relative expression and cellular localization of each contributing to signaling differences in diverse SMC types. Several endogenous ligands, kinases, proteins, and other modulators control SMC IP3R channel activity. SMC IP3Rs communicate with nearby ryanodine-sensitive Ca2+ channels and mitochondria to influence SR Ca2+ release and reactive oxygen species generation. IP3R-mediated Ca2+ release can stimulate plasma membrane-localized channels, including transient receptor potential (TRP) channels and store-operated Ca2+ channels. SMC IP3Rs also signal to other proteins via SR Ca2+ release-independent mechanisms through physical coupling to TRP channels and local communication with large-conductance Ca2+-activated potassium channels. IP3R-mediated Ca2+ release generates a wide variety of intracellular Ca2+ signals, which vary with respect to frequency, amplitude, spatial, and temporal properties. IP3R signaling controls multiple SMC functions, including contraction, gene expression, migration, and proliferation. IP3R expression and cellular signaling are altered in several SMC diseases, notably asthma, atherosclerosis, diabetes, and hypertension. In summary, IP3R-mediated pathways control diverse SMC physiological functions, with pathological alterations in IP3R signaling contributing to disease.
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Atala, Anthony. "Re: PTEN Counteracts FBXL2 to Promote IP3R3- and Ca 2+ -Mediated Apoptosis Limiting Tumour Growth." Journal of Urology 200, no. 1 (July 2018): 31–32. http://dx.doi.org/10.1016/j.juro.2018.04.002.
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Lock, Jeffrey T., Kamil J. Alzayady, David I. Yule, and Ian Parker. "All three IP3receptor isoforms generate Ca2+puffs that display similar characteristics." Science Signaling 11, no. 561 (December 18, 2018): eaau0344. http://dx.doi.org/10.1126/scisignal.aau0344.
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Inositol 1,4,5-trisphosphate (IP3) evokes Ca2+release through IP3receptors (IP3Rs) to generate both local Ca2+puffs arising from concerted openings of clustered IP3Rs and cell-wide Ca2+waves. Imaging Ca2+puffs with single-channel resolution yields information on the localization and properties of native IP3Rs in intact cells, but interpretation has been complicated because cells express varying proportions of three structurally and functionally distinct isoforms of IP3Rs. Here, we used TIRF and light-sheet microscopy to image Ca2+puffs in HEK-293 cell lines generated by CRISPR-Cas9 technology to express exclusively IP3R type 1, 2, or 3. Photorelease of the IP3analog i-IP3in all three cell lines evoked puffs with largely similar mean amplitudes, temporal characteristics, and spatial extents. Moreover, the single-channel Ca2+flux was similar among isoforms, indicating that clusters of different IP3R isoforms contain comparable numbers of active channels. Our results show that all three IP3R isoforms cluster to generate local Ca2+puffs and, contrary to findings of divergent properties from in vitro electrophysiological studies, display similar conductances and gating kinetics in intact cells.
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Xu, Yahang, Xinyue Guo, Shasha Ning, Qian He, Bingran Meng, Fushan Xing, and Yupeng Yin. "Inhibition of IP3R3 attenuates endothelial to mesenchymal transition induced by TGF-β1 through restoring mitochondrial function." Biochemical and Biophysical Research Communications 619 (September 2022): 144–50. http://dx.doi.org/10.1016/j.bbrc.2022.06.033.
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Moschella, M. C., and A. R. Marks. "Inositol 1,4,5-trisphosphate receptor expression in cardiac myocytes." Journal of Cell Biology 120, no. 5 (March 1, 1993): 1137–46. http://dx.doi.org/10.1083/jcb.120.5.1137.
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Calcium release from intracellular stores is the signal generated by numerous regulatory pathways including those mediated by hormones, neurotransmitters and electrical activation of muscle. Recently two forms of intracellular calcium release channels (CRCs) have been identified. One, the inositol 1,4,5-trisphosphate receptors (IP3Rs) mediate IP3-induced Ca2+ release and are believed to be present on the ER of most cell types. A second form, the ryanodine receptors (RYRs) of the sarcoplasmic reticulum, have evolved specialized functions relevant to muscle contraction and are the major CRCs found in striated muscles. Though structurally related, IP3Rs and RYRs have distinct physiologic and pharmacologic profiles. In the heart, where the dominant mechanism of intracellular calcium release during excitation-contraction coupling is Ca(2+)-induced Ca2+ release via the RYR, a role for IP3-mediated Ca2+ release has also been proposed. It has been assumed that IP3Rs are expressed in the heart as in most other tissues, however, it has not been possible to state whether cardiac IP3Rs were present in cardiac myocytes (which already express abundant amounts of RYR) or only in non-muscle cells within the heart. This lack of information regarding the expression and structure of an IP3R within cardiac myocytes has hampered the elucidation of the significance of IP3 signaling in the heart. In the present study we have used combined in situ hybridization to IP3R mRNA and immunocytochemistry to demonstrate that, in addition to the RYR, an IP3R is also expressed in rat cardiac myocytes. Immunoreactivity and RNAse protection have shown that the IP3R expressed in cardiac myocytes is structurally similar to the IP3R in brain and vascular smooth muscle. Within cardiac myocytes, IP3R mRNA levels were approximately 50-fold lower than that of the cardiac RYR mRNA. Identification of an IP3R in cardiac myocytes provides the basis for future studies designed to elucidate its functional role both as a mediator of pharmacologic and hormonal influences on the heart, and in terms of its possible interaction with the RYR during excitation-contraction coupling in the heart.