Purine-Based Inhibitors of Inositol-1,4,5-trisphosphate-3-kinase

Chang, Young‐Tae; Choi, Gildon; Bae, Yoe‐Sik; Burdett, Matthew; Moon, Ho-Sang; Lee, Jae Woo; Gray, Nathanael S.; Schultz, Peter G.; Meijer, Laurent; Chung, Sung‐Kee; Choi, Kwan Yong; Suh, Pann‐Ghill; Ryu, Sung Ho

doi:10.1002/1439-7633(20020902)3:9<897::aid-cbic897>3.0.co;2-b

Cited by 68 publications

(44 citation statements)

References 9 publications

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“…Inhibition of the IP 3 -3K has been shown to elevate intracellular levels of IP 3 by halting its conversion into Ins(1,3,4,5)P4 [23]. Here, to examine the effects of IP 3 signaling on intracellular Zn 2+ dynamics, N 2 -(m-trifluorobenzyl),N 6 -(p-nitrobenzyl)purine, a membrane-permeable inhibitor of IP 3 -3K was employed to confirm the results observed using the caged IP 3 .…”

Section: Resultsmentioning

confidence: 99%

Zinc release from thapsigargin/IP3-sensitive stores in cultured cortical neurons

Stork

2010

JMS

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BackgroundChanges in ionic concentration have a fundamental effect on numerous physiological processes. For example, IP3-gated thapsigargin sensitive intracellular calcium (Ca2+) storage provides a source of the ion for many cellular signaling events. Less is known about the dynamics of other intracellular ions. The present study investigated the intracellular source of zinc (Zn2+) that has been reported to play a role in cell signaling.ResultsIn primary cultured cortical cells (neurons) labeled with intracellular fluorescent Zn2+ indicators, we showed that intracellular regions of Zn2+ staining co-localized with the endoplasmic reticulum (ER). The latter was identified with ER-tracker Red, a marker for ER. The colocalization was abolished upon exposure to the Zn2+ chelator TPEN, indicating that the local Zn2+ fluorescence represented free Zn2+ localized to the ER in the basal condition. Blockade of the ER Ca2+ pump by thapsigargin produced a steady increase of intracellular Zn2+. Furthermore, we determined that the thapsigargin-induced Zn2+ increase was not dependent on extracellular Ca2+ or extracellular Zn2+, suggesting that it was of intracellular origin. The applications of caged IP3 or IP3-3Kinase inhibitor (to increase available IP3) produced a significant increase in intracellular Zn2+.ConclusionsTaken together, these results suggest that Zn2+ is sequestered into thapsigargin/IP3-sensitive stores and is released upon agonist stimulation.

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Section: Resultsmentioning

confidence: 99%

Zinc release from thapsigargin/IP3-sensitive stores in cultured cortical neurons

Stork

2010

JMS

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“…Indeed, several groups have identified small-molecule ITPK inhibitors. Some show high ITPK-selectivity over IPMK33, 109–112.…”

Section: Therapeutic Relevancementioning

confidence: 99%

“…Mast cells express ItpkB and produce IP 4 after stimulation115. Small-molecule ITPK-inhibition might augment their activation24, 109, but the target-selectivity of the low-affinity ITPK-inhibitors used is unknown and genetic studies are needed.…”

Section: Figures and Tablementioning

confidence: 99%

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

2010

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Preface The membrane lipid phosphatidylinositol(3,4,5)trisphosphate (PtdInsP3) regulates membrane receptor signalling in many cells, including immunoreceptor signalling. Here, we review recent data that have indicated essential functions for the soluble PtdInsP3 analogue inositol(1,3,4,5)tetrakisphosphate (InsP4) in T cell, B cell and neutrophil development and function. Decreased InsP4 production in immunocytes causes immunodeficiency in mice and might contribute to inflammatory vasculitis in Kawasaki disease in humans. InsP4-producing kinases could therefore provide attractive drug targets for inflammatory and infectious diseases.

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“…All ITPK inhibitors described so far interact with either the Ins(1,4,5)P 3 or ATP recognition sites in the catalytic domain [199][200][201]. Early attempts to identify inhibitory lead compounds employed exhaustive screens of inositol phosphate isomers [199,202].…”

Section: The Potential Of Itpk-based Therapiesmentioning

confidence: 99%

“…Screens of purine-based inhibitors acting at the ATP site have identified possible lead compounds for ITPK inhibition, but the likely problem here is lack of selectivity over other types of kinases, especially other members of the IPK family [203,204]. Indeed, a promising purinebased lead compound for ITPKA inhibition [200] was later shown to be a significantly more potent inhibitor of InsP 6 kinase [205]. The structural similarity of the ITPK ATPbinding site with an ancient kinase family emphasizes the difficulties of obtaining selectivity at the ATP site [23].…”

Section: The Potential Of Itpk-based Therapiesmentioning

confidence: 99%

Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling

Schell

2010

Cell. Mol. Life Sci.

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The localized control of second messenger levels sculpts dynamic and persistent changes in cell physiology and structure. Inositol trisphosphate [Ins(1,4,5)P(3)] 3-kinases (ITPKs) phosphorylate the intracellular second messenger Ins(1,4,5)P(3). These enzymes terminate the signal to release Ca(2+) from the endoplasmic reticulum and produce the messenger inositol tetrakisphosphate [Ins(1,3,4,5)P(4)]. Independent of their enzymatic activity, ITPKs regulate the microstructure of the actin cytoskeleton. The immune phenotypes of ITPK knockout mice raise new questions about how ITPKs control inositol phosphate lifetimes within spatial and temporal domains during lymphocyte maturation. The intense concentration of ITPK on actin inside the dendritic spines of pyramidal neurons suggests a role in signal integration and structural plasticity in the dendrite, and mice lacking neuronal ITPK exhibit memory deficits. Thus, the molecular and anatomical features of ITPKs allow them to regulate the spatiotemporal properties of intracellular signals, leading to the formation of persistent molecular memories.

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Purine-Based Inhibitors of Inositol-1,4,5-trisphosphate-3-kinase

Cited by 68 publications

References 9 publications

Zinc release from thapsigargin/IP3-sensitive stores in cultured cortical neurons

Zinc release from thapsigargin/IP3-sensitive stores in cultured cortical neurons

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

Inositol trisphosphate 3-kinases: focus on immune and neuronal signaling

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