Inositol 1,3,4,5-tetrakisphosphate is essential for T lymphocyte development.

Inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) is phosphorylated by Ins(1,4,5)P(3) 3-kinase, generating inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P(4)). The physiological function of Ins(1,3,4,5)P(4) is still unclear, but it has been reported to be a potential modulator of calcium mobilization. Disruption of the gene encoding the ubiquitously expressed Ins(1,4,5)P(3) 3-kinase isoform B (Itpkb) in mice caused a severe T cell deficiency due to major alterations in thymocyte responsiveness and selection. However, we were unable to detect substantial defects in Ins(1,4,5)P(3) amounts or calcium mobilization in Itpkb(-/-) thymocytes. These data indicate that Itpkb and Ins(1,3,4,5)P(4) define an essential signaling pathway for T cell precursor responsiveness and development.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) controls survival, proliferation and cytokine production in mouse peripheral T cells

Mice genetically-deficient for the B isoform of the inositol 1,4,5-trisphosphate 3-kinase (or Itpkb) have a severe defect in thymocytes differentiation and thus lack peripheral T cells. In order to study the functional role of Itpkb in peripheral T cells, we constructed a new mouse where a transgene encoding mouse Itpkb is specifically and transiently expressed in thymocytes of Itpkb-/- mice. This allows a partial rescue of mature thymocyte/T cell differentiation and thus the functional characterization of peripheral T cells lacking Itpkb. We show here that Itpkb-/- CD4+ and CD8+ peripheral T cells present important functional alterations. Indeed, an increased activated/memory phenotype as well as a decreased proliferative capacity and survival were detected in these T cells. These Itpkb-deficient peripheral T cells have also an increased capacity to secrete cytokines upon stimulation. Together, our present results define the important role of Itpkb in peripheral mature T cell fate and function in mouse, suggesting a potential role for Itpkb in autoimmunity

Regulation of the localization and activity of inositol 1,4,5-trisphosphate 3-kinase B in intact cells by proteolysis

IP3K (inositol 1,4,5-trisphosphate 3-kinase) catalyses the Ca(2+)-regulated phosphorylation of the second messenger Ins(1,4,5)P(3), thereby inactivating the signal to release Ca(2+) and generating Ins(1,3,4,5)P(4). Here we have investigated the localization and activity of IP3KB and its modulation by proteolysis. We found that the N- and C-termini (either side of residue 262) of IP3KB localized predominantly to the actin cytoskeleton and ER (endoplasmic reticulum) respectively, both in COS-7 cells and in primary astrocytes. The functional relevance of this was demonstrated by showing that full-length (actin-localized) IP3KB abolished the histamine-induced Ca(2+) response in HeLa cells more effectively than truncated constructs localized to the ER or cytosol. The superior efficacy of full-length IP3KB was also attenuated by disruption of the actin cytoskeleton. By transfecting COS-7 cells with double-tagged IP3KB, we show that the translocation from actin to ER may be a physiologically regulated process caused by Ca(2+)-modulated constitutive proteolysis in intact cells

Neuromuscular electrical stimulation of completely paralyzed abdominal muscles in spinal cord-injured patients: A pilot study

Study Design: Prospective placebo-controlled. Objective: The effect of abdominal neuromuscular electrical stimulation (NMES) in patients with spinal cord injury. The principal parameters observed in this study are lung capacity, colonic transit, patient satisfaction of used method and of aesthetics effect on abdominal wall. Settings: Centre de Traumatologie et de Réadaptation, Brussels, Belgium. Methods: A total of 10 volunteers participated in this study and were assigned to two groups - the effective electrical stimulation group (ESG) and the placebo-controlled group (PG). NMES of abdominal muscles was performed 25 min per day for 8 weeks. Results: NMES significantly decreased forced vital capacity (FVC) in ESG but not in PG. In ESG, colonic transit was accelerated in ascending, transverse and descending colon but transit in rectosigmoideum was not affected. In PG, no variations in colonic transit were observed. Satisfaction scale shows a better influence on aesthetics effect in ESG than in PG. Conclusion: This pilot study shows that NMES of paralyzed abdominal muscles positively affects colonic transit except in rectosigmoideum segment and negatively affects FVC. It could be a simple self-used method to regulate colonic transfer with considerably good cosmetic effect on abdominal wall. However, regular verification of FVC will probably be necessary. © 2008 International Spinal Cord Society All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Inositol(1,4,5)P3 3-kinase isoenzymes: Catalytic properties and importance of targeting to F-actin to understand function.

Inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) 3-kinases (Itpks) catalyze the phosphorylation of inositol(1,4,5)trisphosphate into inositol(1,3,4,5)tetrakisphosphate (Ins(1,3,4,5)P4). Three isoenzymes Itpka/b and c have been identified in human, rat and mouse. They share a catalytic domain relatively well conserved at the C-terminal end and a quite isoenzyme specific regulatory domain at the N-terminal end of the protein. Activity determined in cell homogenates with Ins(1,4,5)P3 and ATP as substrate is generally very low compared to Ins(1,4,5)P3 5-phosphatase, except in a few tissues such as brain, testis, thymus or intestine. Activity is very much Ca(2+) sensitive and increased in the presence of Ca(2+)/calmodulin (CaM) as compared to EGTA alone. When challenged after receptor activation, activity could be further activated several fold, e.g. in rat brain cortical slices stimulated by carbachol or in human astrocytoma cells stimulated by purinergic agonists. Two of the three isoenzymes show an unexpected cytoskeletal localization for Itpka/b or at the leading edge for Itpkb. This is explained by the presence of an F-actin binding site at the N-terminal part of the two isoenzymes. This interaction confers to Itpka the properties of an F-actin bundling protein with two major consequences: i) it can reorganize the cytoskeletal network, particularly in dendritic spines, and ii) can provide an opportunity for Ins(1,3,4,5)P4 to act very locally as second messenger.info:eu-repo/semantics/publishe

Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology

S. Schurmans and J.-P. Brion contributed equally to this work Corresponding author: S. Schurmans, Laboratoire de Génétique Fonctionnelle, GIGA-Research Centre, Building 34, Université de Liège, rue de l’Hôpital 1, 4000-Liège, Belgium. Abstract: Inositol (1,4,5) trisphosphate 3-kinase B phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that Inositol (1,4,5) trisphosphate 3-kinase B mRNA level is significantly increased in the cerebral cortex of Alzheimer patients, compared to control subjects. Since Extracellular signal-regulated kinases 1/2 activation is increased in Alzheimer brain and since Inositol (1,4,5) trisphosphate 3-kinase B is a regulator of Extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer’s disease might be related to an increased activity of Inositol (1,4,5) trisphosphate 3-kinase B. We show here that Inositol (1,4,5) trisphosphate 3-kinase B protein level was 3 fold increased in the cerebral cortex of most Alzheimer patients, compared to control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Inositol (1,4,5) trisphosphate 3-kinase B overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to amyloid-β peptides overproduction. In this cellular model, an inhibitor of Mitogen-activated kinase kinases 1/2 completely prevented amyloid-β peptides overproduction. Transgenic overexpression of Inositol (1,4,5) trisphosphate 3-kinase B in mouse forebrain neurons was not sufficient to induce amyloid plaques formation or TAU hyperphosphorylation. However, in the 5X Familial Alzheimer’s Disease mouse model, neuronal Inositol (1,4,5) trisphosphate 3-kinase B overexpression significantly increased Extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer pathology as shown by increased astrogliosis, amyloid-β40 peptide production and TAU hyperphosphorylation. No impact on pathology was observed in the 5X Familial Alzheimer’s Disease mouse model when a catalytically inactive Inositol (1,4,5) trisphosphate 3-kinase B protein was overexpressed. Together, our results point to the Inositol (1,4,5) trisphosphate 3-kinase B /Inositol 1,3,4,5-tetrakisphosphate/Extracellular signal-regulated kinases 1/2 signaling pathway as an important regulator of neuronal cell apoptosis, Amyloid precursor protein processing and TAU phosphorylation in Alzheimer’s disease, and suggest that Inositol (1,4,5) trisphosphate 3-kinase B could represent a new target for reducing pathology in human AD patients with increased cortical Inositol (1,4,5) trisphosphate 3-kinase B expression