Disease relevance of ITPR1

• The antagonist of IP3R, 2APB, inhibited cell proliferation and induced apoptosis in gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose-dependent manner [1].
• Antibodies directed against the ryanodine receptor or the IP3 receptor reacted with the great majority of neurons in the ganglion cell layer [2].
• In the two cerebella obtained from patients suffering from ataxia, a several-fold reduction of immunostaining with IP3R1 was found [3].
• Western blotting revealed that in hyperthermia there was initial release of Ca(2+) from the intracellular store site as indicated by increased expression of the type 1 inositol-1,4,5-trisphosphate receptor [4].
• The results show that multiple IP3R types are expressed in osteoblasts and osteoblastic osteosarcoma cells and that this expression is regulated by 17 beta-estradiol and other osteoporotic and antiosteoporotic hormones [5].

Psychiatry related information on ITPR1

• To determine whether InsP3R1/NCS-1 interaction could be functionally relevant in bipolar disorders, conditions in which NCS-1 is highly expressed, we tested the effect of lithium, a salt widely used for treatment of bipolar disorders [6].
• Several studies have shown severe deficits in both IP3 receptor levels and PKC levels and activity in Alzheimer's disease brain, although the relationship of these changes to disease pathology is poorly understood [7].

High impact information on ITPR1

• The inositol 1,4,5 trisphosphate (IP3) receptor (IP3R) is a Ca2+ release channel that responds to the second messenger IP3 [8].
• Through these regulatory mechanisms, IP3R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, secretion, gene expression, and cellular growth [8].
• We review the unique properties of the IP3R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners [8].
• Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta [9].
• Calcium release from inositol 1,4,5-trisphosphate (IP3)-sensitive stores is negatively regulated by binding of calmodulin to the IP3 receptor (IP3R) and the NO/cGMP/cGMP kinase I (cGKI) signalling pathway [9].

Chemical compound and disease context of ITPR1

• Here we demonstrate that calphostin C induces dose-dependent apoptosis in DT40 chicken lymphoma B-cells, and targeted disruption of lyn, syk, btk, PLCgamma2, or IP3R genes does not prevent or attenuate its cytotoxicity [10].
• Such selective inhibition of inositol 1,4,5-trisphosphate receptor-induced Ca2+ release and the loss of type 1 inositol 1,4,5-trisphosphate receptor in the CA1 region of the hippocampus in cerebral ischemia may be associated with its region-specific vulnerability to ischemia [11].
• In this study, we examined the effect of chronic ethanol on mRNA levels of sarcoplasmic or endoplasmic Ca2+-ATPase (SERCA2b) and inositol 1,4, 5-triphosphate receptor (IP3R1) in gerbils subjected to global cerebral ischemia induced by ligation of both common carotid arteries [12].
• Changes of inositol 1,4,5-trisphosphate receptor (IP3R) mRNA expression after transient brain ischemia and the effect of MK-801, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, on the IP3R mRNA expression was studied in mongolian gerbil brain by in situ hybridization [13].
• More importantly, IP3R inhibitors, 2-aminoethoxydiphenyl borate and Xestospongin C, abolished the IP3BM-induced Ca2+ responses, and significantly suppressed alpha1AR-induced cardiomyocyte hypertrophy assayed by cell size, [3H] leucine incorporation and atrial natriuretic factor gene expression, during sustained (48 h) phenylephrine stimulation [14].

Biological context of ITPR1

• In addition, identification of a CyB docking site(s) on IP3R1 demonstrates, for the first time, a direct interaction between a cell cycle component and an intracellular calcium release channel [15].
• The calcium signals mediated by RyR and IP3R are very different in kinetics, amplitude and subcellular localization; an open question is whether these differences are differentially sensed by transcription factors [16].
• Data from our laboratory have linked IP3R expression with susceptibility to apoptosis [17].
• Regulation of the type 1 inositol 1,4,5-trisphosphate receptor by phosphorylation at tyrosine 353 [18].
• Engagement of the T cell or B cell receptor by antigen initiates a signal transduction cascade that leads to tyrosine phosphorylation of IP3R by Src family nonreceptor protein tyrosine kinases, including Fyn [18].

Anatomical context of ITPR1

• Thrombin also induced translocation of a complex consisting of Rho, IP3R, and TRPC1 to the plasma membrane [19].
• These results indicate that RYR1 functions as a Ca2+ release channel during BCR-stimulated Ca2+ signaling and suggest that complex Ca2+ signals that control the cellular activities of B cells may be generated by cooperation of the IP3 receptor and RYR1 [20].
• We tested the hypothesis that RhoA, a monomeric GTP-binding protein, induces association of inositol trisphosphate receptor (IP3R) with transient receptor potential channel (TRPC1), and thereby activates store depletion-induced Ca2+ entry in endothelial cells [19].
• Rho-induced association of IP3R with TRPC1 was dependent on actin filament polymerization because latrunculin (which inhibits actin polymerization) prevented both the association and Ca2+ entry [19].
• Our results indicate that the activation of SOC in keratinocytes depends, at least partly, on the interaction of TRPC with PLCgamma1 and IP3R [21].

Associations of ITPR1 with chemical compounds

• Heparin inhibition of endogenous inositol trisphosphate receptors (IP3R) had little effect on intracellular Ca2+ handling or viability [22].
• Thus, caffeine may act as an inhibitor on a single or multiple site(s) responsible for regulating the IP3R channel, RYR channel and presumably the receptor-mediated SOC channel [23].
• The inositol 1,4,5-trisphosphate receptor (IP3R) is an endoplasmic reticular calcium release channel found in most cell types [17].
• IP3R-deficient T cells are resistant to apoptosis induced by dexamethasone, T cell receptor stimulation, ionizing radiation, and Fas [17].
• During T cell activation the IP3R was tyrosine phosphorylated [24].

Physical interactions of ITPR1

• Conformational coupling with the inositol 1,4,5-trisphosphate (IP3) receptor has been suggested as a possible mechanism of activation of TRPC3 channels and a region in the C terminus of TRPC3 has been shown to interact with the IP3 receptor as well as calmodulin (calmodulin/IP3 receptor-binding (CIRB) region) [25].
• Multiserine phosphorylation of IRBIT was essential for the binding, and 10 of the 12 key amino acids in IP3R for IP3 recognition participated in binding to IRBIT [26].
• We now report that FKBP12 binds the IP3R at residues 1400-1401, a leucyl-prolyl dipeptide epitope that structurally resembles FK506 [27].

Enzymatic interactions of ITPR1

• The IP3 receptor is stoichiometrically phosphorylated by protein kinase C (PKC) and Ca2+ calmodulin-dependent protein kinase II (CaM kinase II) as well as by PKA [28].

Co-localisations of ITPR1

• Moreover, IP3-R was translocated to and colocalized with EB aggregates and chlamydial inclusions and had a distribution very similar to that of SERCA 2 [29].

Regulatory relationships of ITPR1

• In the present study, we showed that IRBIT suppresses the activation of IP3R by competing with IP3 by [3H]IP3 binding assays, in vitro Ca2+ release assays, and Ca2+ imaging of intact cells [26].

Other interactions of ITPR1

• These molecular data are in agreement with the lack of correlation between FKBP12 and IP3R1 expression in various cell types [30].
• Using wild-type IP3R1 or an IP3R1-Y353F mutant that cannot be tyrosine phosphorylated at Tyr353 or expressed in IP3R-deficient DT40 B cells, we demonstrated that tyrosine phosphorylation of Tyr353 permits prolonged intracellular Ca2+ release during B cell activation [18].
• A calmodulin/inositol 1,4,5-trisphosphate (IP3) receptor-binding region targets TRPC3 to the plasma membrane in a calmodulin/IP3 receptor-independent process [25].
• 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 [31].
• Binding of IRBIT to the IP3 receptor: determinants and functional effects [32].

Analytical, diagnostic and therapeutic context of ITPR1

• By immunofluorescence, the IP3 receptor type 1 (IP3R-1) was distributed over the endoplasmic reticulum and codistributed with CALNUC in the Golgi [33].
• Molecular cloning of a cDNA for the human inositol 1,4,5-trisphosphate receptor type 1, and the identification of a third alternatively spliced variant [34].
• PCR analysis of brain and peripheral tissues from human and rat shows both transcripts of the type 1 inositol 1,4,5-trisphosphate receptor in all tissues [34].
• Sequence analysis of IP3R1 reveals the presence of two putative phosphorylation sites for cyclin-dependent kinases (cdks) [35].
• In situ hybridization localized both RyR and IP3R mRNAs to human cardiac myocytes [36].

References