PKC activators

Protection appears to be mediated by PKC activation. Radiation induces b-EGE production by these cells, allowing a survival-associated positive autocrine loop to develop. 

Activation of PI-PLC-linked receptors, such as the mAChR, results in increased PKC activity. Since the addition of phorbol esters, which are PKC agonists (see Ch. 20), results in phosphorylation of Raf, this mechanism may provide an explanation for the ability of PI-PLC-coupled receptors to activate MAPK. A recently discovered protein tyrosine kinase PYK2, which is enriched in the CNS, is also activated by PKC. Like PTK-X, PYK2 phosphorylates SHC and recruits the Grb2-SOS complex, which results in activation of the MAPK cascade. PYK2 is also activated by... 

H, receptors in brain slices can also stimulate glycogen metabolism [5] and can positively modulate receptor-linked stimulation of cAMP synthesis. The activation of brain cAMP synthesis by histamine is a well studied phenomenon that reveals a positive interaction between histamine receptors [35]. When studied in cell-free preparations, this response shows characteristics of H2, but not H receptors. When similar experiments are performed in brain slices, however, both receptors appear to participate in the response. Subsequent work showed that H receptors do not directly stimulate adenylyl cyclase but enhance the H2 stimulation, probably through the effects of calcium and PKC activation on sensitive adenylyl cyclase iso forms (see Ch. 21). 

In addition, the phosphotyrosine moiety (Y402) on a proline-rich tyrosine kinase (PYK2, a NRPTK) can apparently compete with phosphoY527 for interaction with SH2 domain on Src and lead to Src activation. PYK2 is a member of the Fak family. It is highly expressed in the nervous system. Its activation depends on both cell adhesion and the presence of calcium or PKC activation. Therefore, certain G-protein-coupled receptors (GPCRs)... 

To date, there have only been a limited number of studies directly examining PKC in bipolar disorders [77], Although undoubtedly an oversimplification, particulate (membrane) PKC is sometimes viewed as the more active form of PKC, and thus an examination of the subcellular partitioning of this enzyme can be used as an index of the degree of activation. Friedman etal. [78] investigated PKC activity and PKC translocation in response to serotonin in platelets obtained from bipolar-disorder patients before and during lithium treatment. They reported that the ratios of platelet-membrane-bound to cytosolic PKC activities were elevated in the manic patients. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those patients. With respect to brain tissue, Wang and Friedman [74] measured PKC isozyme levels, activity and translocation in postmortem brain tissue from patients with bipolar disorder, and reported increased PKC activity and translocation in the brains of bipolar patients compared with controls, effects which were accompanied by elevated levels of selected PKC isozymes in cortices of bipolar disorder patients. 

Evidence accumulating from various laboratories has clearly demonstrated that lithium, at therapeutically relevant concentrations, exerts significant effects on the PKC signaling cascade. Current data suggest that chronic lithium attenuates PKC activity, and down-regulates the expression of PKC isozymes V in the frontal cortex and hippocampus [79, 80], Chronic lithium has also been demonstrated to dramatically reduce the hippocampal levels of a major PKC substrate, myristoylated-alanine-rich C kinase substrate (MARCKS), which has been implicated in regulating long-term neuroplastic events. 

The short-term increase in DAG levels following acute Li+ administration is proposed to account for the subsequent enhanced activation of PKC, facilitating the release of certain neurotransmitters. PKC undergoes rapid proteolysis after its activation and it is proposed that chronic Li+ treatment, producing prolonged increases in DAG levels, actually downregulates PKC activity and attenuates neurotransmitter release... 

Commensurately with the development of various catalyst systems, the Pd-catalyzed G-O cross-coupling has found a number of synthetic applications. Examples include the syntheses of the protein kinase G (PKC) activator (+)-decursin,104 the natural product heliannuol E,105 a chiral 2-methyl chroman,106 and a series of aryloxy and alkoxy porphyrins.107 The Buchwald-Hartwig coupling has also been utilized in the preparation of a heterocycle library.108 Intramolecular O-arylation has also been achieved in the reactions of enolates with aryl halides leading to benzofur-ans.109,110 Finally, a double cross-coupling between an 0-dibromobenzene and a glycol has also been applied for the preparation of benzodioxanes (Equation (16)).1... 

Nelson Yes, but it was sustained over tens of minutes. Clearly, in the first few minutes if the SR is depleted this may contribute to the initial suppression but the tonic effect appeared to reflect PKC activation. 

This ceramide-mediated apoptosis was shown to be inhibited by the simultaneous addition of PKC activators (Ni et at, 1994 Obeid et al, 1993), implying that PS may activate the ceramide-mediated apoptotic pathway. However, the inhibitors of interleukin-1 converting enzyme (ICE)-like proteases (Caspase), such as tosyl-L-lysine chloromethyl ketone (TLCK), and tosyl-L-phenylalanine chloromethyl ketone (TPCK) which inhibit ceramide-mediated apoptosis, had no effect on PS-induced apoptosis (Figure 4). Thus, PS-induced apoptotic pathway appears to be distinct from that mediated by ceramide. Further studies are required to clarify the molecular mechanisms underlying the PS-induced apoptosis. 

In previous studies it has been demonstrated that not only protein kinase C (PKC) activators including phorbol esters (TPA) and diacylglycerol (DAG) inhibited the ability of cell-permeant CER to induce apoptosis (Jarvis et al. 1996), but also that PKC inhibitors enhanced CER-induced apoptosis (Jarvis et al, 1994). From these studies it has been suggested that PKC is a key negative regulator of CER-induced apoptosis. 

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