Inositol 1,4,5-triphosphate 3-kinase

Shin, Y.S. Choi, G. Choi, K.Y. Overexpression, purification and characterization of inositol 1,4,5-triphosphate 3-kinase from rat brain. Mol. Cells, 5, 348-353 (1995)... 

Mailleux P, Takazawa K, Erneux C, Vanderhaegben JJ (1991b) Inositol 1,4, 5-triphosphate 3-kinase mRNA high levels in the rat hippocampal CAI pyramidal and dentate gyrus granule cells and in cerebellar Purkinje cells. J. Neurochem., 56, 345-347. 

Mayr, G.W., Windhorst, S., and Hillemeier, K. 2005. Antiproliferativeplant and synthetic polyphenolics are specific inhibitors ofvertebrate inositol-1,4,5-triphosphate 3-kinases and inositol polyphosphatemultikinase , 5. B/o/. Chem., 250 13229-13240. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Another type of NR crosstalk, which has only recently been recognized, is the so-called nongenomic actions of several receptors that induce very rapid cellular effects. Effectively, evidence has accumulated over several decades that steroid receptors may have a role that does not require their transcriptional activation, such as modifying the activity of enzymes and ion channels. While the effects of steroids that are mediated by the modulation of gene expression do occur with a time lag of hours, steroids can induce an increase in several second messengers such as inositol triphosphate, cAMP, Ca2+, and the activation of MARK and PI3 kinase within seconds or minutes. Many mechanistic details of these nongenomic phenomena remain poorly understood. Notably, controversy still exists as to the identity of the receptors that initiate the non-genomic steroid actions. However, it now appears that at least some of the reported effects can be attributed to the same steroid receptors that are known as NRs. 

There is evidence for immunosuppressive effects of PAHs in rodents (Davila et al. 1997). For example, strong immunosuppressive effects were reported in mice that had been dosed with benzo[fl]pyrene and 3-methyl cholanthrene, effects that persisted for up to 18 months (Environmental Health Criteria 202). Multiple immu-notoxic effects have been reported in rodents, and there is evidence that these result from disturbance of calcium homeostasis (Davila et al. 1997). PAHs can activate protein tyrosine kinases in T cells that initiate the activation of a form of phospholipase C. Consequently, release of inositol triphosphate—a molecule that immobilizes Ca + from storage pools in the endoplasmic reticulum—is enhanced. 

When the receptor interacts with its associated G protein, the conformation of the guanine-nucleotide-binding site is altered. The subunits then dissociate, and a phosphatidylinositol-specific phospholipase C (PI-PLC) is activated [5]. The subsequent hydrolysis of phosphatidylinositol bisphosphate then produces inositol triphosphate (IP3) and diacylglycerol (DAG), which are known to be secondary messengers. For example, the water soluble IP3 is released into the cell where its ultimate targets are the calcium storage organelles from which Ca2+ is released [3]. The presence of DAG in cells is known to activate the cellular enzyme protein kinase C (PKC) [6, 7], which phosphorylates a number of cellular... 

Figure 4.13. Model of peptide initiation of mast secretion. Insertion of the hydrophobic region of the peptide into the lipid bilayer properly orients the basic (+) groups at the N-terminus for binding to negatively charged membrane components. As a result, there is activation of the G protein complex with the subsequent generation of inositol triphosphate (IP ) and diacylglycerol (DAG). These intermediates then stimulate the mobilization of cellular Ca and possibly the transient influx of extracellular Ca as well as the activation ofprotein kinase C. As a consequence, the level of intracellular free ionized Ca is maintained at an elevated state. The end result is the exocytotic extrusion of secretory granules.

There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the posts)maptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the s)mthesis of trophic factors is... 

Platelet activation occurs in large part via G protein-coupled agonist receptors and intracellular signaling events that involve activation of phospholipase C (PLC). PLC catalyzes the breakdown of plasma membrane inositol phospholipids, resulting in generation of 1,2-diacylglycerol (DAG) and 1,4,5-inositol triphosphate (IP3). DAG activates protein kinase C, and IP3 induces mobilization of calcium from intracellular stores (10). 

Inositol triphosphate (IP3), which raises intracellular Ca + concentrations by inducing its release from intracellular stores. This Ca +, in turn, activates a cytoplasmic serine/ threonine protein kinase. 

IP3 = 1,4,5-inositol triphosphate PI = phosphatidylinositol PIP = phosphatidylinositol phosphate PIP2 = phosphatidylinositol 4,5-biphosphate PKC = protein kinase C PLC = phosphohpase C R = receptor T = transporter. 

Inositol triphosphate is water soluble and therefore diffuses into the cytoplasm, where it mobilizes calcium from its stores in microsomes or the endoplasmic reticulum. The Ca ions then activate Ca-dependent kinases (like troponin C in muscle) directly or bind to the ubiquitous Ca-binding protein calmodulin, which activates calmodulin-dependent kinases. These kinases, in turn, phosphorylate cell-specific enzymes. 

Figure 1.11 Pathways involved in phospholipase C (PLC) cellular signalling. PKA, protein kinase A or cAMP-dependent protein kinases PKC, protein kinase C PI, phosphatidylinositol PIP2, phosphatidylinositol bis-phosphate IP3, inositol triphosphate IP, inositol phosphate DAG, diacylglycerol.

Furthermore, the LPS signal transduction involves the activation of G proteins, of phospholipases C and D, the formation of diacyl-glycerol (DG) and inositol triphosphate (IP3). DG mediates the stimulation of protein kinase C (PKC) and IP3 induces an increase of cytosolic Ca++ The LPS signaling pathway also involves tyrosine kinases, constitutive nitric oxide (NO) synthase (cNOS), cGMP-dependent protein kinase, Ca channels, calmodulin and calmodulin kinase [27,28], as well as the MAP kinases [29] ERK1, ERK2 and p38 [23], The intracellular events in response to LPS are due to lipid A because they are inhibited by polymyxin B which is known to bind lipid A [27] and they are reproduced by lipids A [30,31]. 

In addition to JAKs, STAT1 is also directly phosphorylated by protein kinase C. This process is mediated by inositol triphosphate, Ca2+ release, formation of Ca2+-calmodulin complex and release of calcineurin. Calcineurin dephosphorylates NF-AT resulting in its translocation to the nucleus and subsequent activation of STAT1, in addition to other genes. 

Figure 32.4. Cyclosporin A (CsA) disruption of signal transduction pathways leading to IL-2 production. CsA binds to cyclophilin in the cytoplasm. The complex disrupts at least two signaling pathways, decreasing activation of transcription factors AP-1 and NF-AT that lead to activation of genes involved in cytokine production. See text for detailed explanation. Abbreviations TCR, T-cell receptor PLC, phospholipase C IP3, inositol triphosphate PKC, protein kinase C DAG, diacylglycerol NF-AT, nuclear factor of activation PI, phophati-dylinositol PC, phosphatidylcholine.

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