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Protein Kinase C. (protein + kinase_c)
Selected AbstractsActivation of class I metabotropic glutamate receptors limits dendritic growth of Purkinje cells in organotypic slice culturesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2006Alexandra Sirzen-Zelenskaya Abstract The development of the dendritic tree of a neuron is a complex process which is thought to be regulated strongly by signals from afferent fibers. We showed previously that the blockade of glutamatergic excitatory neurotransmission has little effect on Purkinje cell dendritic development. We have now studied the effects of glutamate receptor agonists on the development of Purkinje cell dendrites in mouse organotypic slice cultures. The activation of N -methyl- d -aspartate receptors had no major effect on Purkinje cell dendrites and the activation of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptors was strongly excitotoxic so that no analysis of its effects on dendritic development was possible. The activation of metabotropic glutamate receptors led to a very strong inhibition of dendritic growth, resulting in Purkinje cells with very small stubby dendrites. This effect was specific for the activation of class I metabotropic glutamate receptors and could not be reduced by blocking synaptic transmission in the cultures, indicating that it was mediated by receptors present on Purkinje cells. Pharmacological experiments suggest that the signaling pathway involved does not require activation of phospholipase C or protein kinase C. The inhibition of dendritic growth by activation of class I metabotropic glutamate receptor could be a useful negative feedback mechanism for limiting the size of the dendritic tree of Purkinje cells after the establishment of a sufficient number of parallel fiber contacts. This developmental mechanism could protect Purkinje cells from excitotoxic death through excessive release of glutamate from an overload of parallel fiber contacts. [source] Deficits in the mid-brain raphe nuclei and striatum of the AS/AGU rat, a protein kinase C-, mutantEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2005M. Al-Fayez Abstract The AS/AGU rat carries a recessive mutation (agu) in the gene coding for the gamma isoform of protein kinase C. The rat is characterized by disordered locomotion and progressive dysfunction of the nigrostriatal dopaminergic (DA) system. This dysfunction begins with a failure to release DA within the striatum and culminates in cell loss within the substantia nigra pars compacta. The present study examines another midbrain aminergic system with input to the basal ganglia, the serotonergic (5-HT) raphe,striatal system originating in the dorsal raphe nucleus. By 3 months after birth, there is a very substantial reduction in the extracellular levels of 5-HT in the dorsal caudate-putamen of the mutants compared with controls (c. 70%). This is accompanied by a proportional increase in the levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA). At a later age, there are reductions in whole tissue 5-HT (and increases in 5-HIAA) in both the striatum and the region containing the dorsal raphe nucleus, as well as numbers of 5-HT-immunoreactive cells in the dorsal raphe nucleus. The median raphe appears to be unaffected. The results are seen in terms of an initial dysfunction in transmitter release leading to cell death, perhaps through the formation of free radicals or neurotoxins. [source] Cytotoxic action of phorbol esters on human pancreatic cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 7 2007Jane A. Bond Abstract We previously showed that phorbol esters are cytotoxic to human thyroid epithelial cells expressing a mutant RAS oncogene. Here we explore the generality of this finding using cells derived from pancreatic cancer, which, like thyroid, shows a high frequency of RAS mutation, but is a much greater cause of cancer mortality. The response to phorbol myristate acetate (PMA) and related agents was assessed on a panel of 9 pancreatic cancer cell lines, using a range of assays for cell growth and death in vitro and in vivo. In most lines, PMA induced non-apoptotic cell death which was, surprisingly, independent of its "classic" target, protein kinase C. With 24 hr exposure, the IC50 in the most sensitive line (Aspc-1) was <1 ng/ml (1.6 nM), with survival undetectable at concentrations ,,16 nM, and after only 1 hr exposure the IC50 was still ,,16 nM. Interestingly, the efficacy of a second phorbol ester, phorbol dibutyrate, was much lower, and the PMA analogue bryostatin-1, which is in clinical trials against other tumour types, was totally inactive. Pre-treatment of Aspc-1 cells with PMA before subcutaneous inoculation into nude mice prevented, or greatly retarded, subsequent xenograft tumour growth. Furthermore, treatment of established tumours with a single peri-tumoral injection of PMA induced extensive cell death and arrested tumour development. Taken together with recent Phase 1 clinical studies, these data suggest that activity against pancreatic cancer will be attainable by systemic administration of PMA, and point to potential novel therapeutic targets for this highly aggressive cancer. © 2007 Wiley-Liss, Inc. [source] Updating the effects of fatty acids on skeletal muscleJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2008Leonardo R. Silveira In this review we updated the fatty acid (FA) effects on skeletal muscle metabolism. Abnormal FA availability induces insulin resistance and accounts for several of its symptoms and complications. Efforts to understand the pathogenesis of insulin resistance are focused on disordered lipid metabolism and consequently its effect on insulin signaling pathway. We reviewed herein the FA effects on metabolism, signaling, regulation of gene expression and oxidative stress in insulin resistance. The elevated IMTG content has been associated with increased intracellular content of diacylglycerol (DAG), ceramides and long-chain acyl-coenzyme A (LCA-CoA). This condition has been shown to promote insulin resistance by interfering with phosphorylation of proteins of the insulin pathway including insulin receptor substrate-1/2 (IRS), phosphatidylinositol-3-kinase, (PI3-kinase) and protein kinase C. Although the molecular mechanism is not completely understood, elevated reactive oxygen (ROS) and nitrogen species (RNS) are involved in this process. Elevated ROS/RNS activates nuclear factor-kappaB (NFkB), which promotes the transcription of proinflammatory tumoral necrosis factor alpha (TNF,), decreasing the insulin response. Therefore, oxidative stress induced by elevated FA availability may constitute one of the major causes of insulin resistance in skeletal muscle. J. Cell. Physiol. 217: 1,12, 2008. © 2008 Wiley-Liss, Inc. [source] Activation of Arylalkylamine N -Acetyltransferase by Phorbol Esters in Bovine Pinealocytes Suggests a Novel Regulatory Pathway in Melatonin SynthesisJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2004C. Schomerus Abstract In all mammalian species investigated, noradrenaline activates a ,-adrenoceptor/cAMP/protein kinase A-dependent mechanism to switch on arylalkylamine N -acetyltransferase and melatonin biosynthesis in the pineal gland. Other compounds which are known to influence the melatonin-generating system are phorbol esters. The effect of phorbol esters on regulation of melatonin synthesis has been mainly investigated in rat pinealocytes. In these cells, phorbol esters do not increase cAMP levels and arylalkylamine N -acetyltransferase on their own; however, phorbol esters potentiate the effects on cAMP and AANAT activity induced upon ,-adrenoceptor stimulation. In the present study, we investigated the effect of phorbol esters on the regulation of melatonin synthesis in bovine pinealocytes. We show that, in these cells, the phorbol esters 4,-phorbol 12-myristate 13-acetate (PMA) or phorbol 12,13-dibutyrate have a direct stimulatory effect and induced 4,10-fold increases in AANAT protein levels, AANAT activity and melatonin production. The extent of these effects was similar to those induced by noradrenaline. Notably, responses to PMA were not accompanied by increases in cAMP levels. Northern blot analysis showed that Aanat mRNA levels did not change upon PMA treatment indicating that phorbol esters control AANAT at a post-transcriptional level. The effects on AANAT and melatonin production were reduced by use of protein kinase C inhibitors, but not by blockade of the cyclic AMP/protein kinase A pathway. Our results point towards a novel mechanism in the regulation of melatonin production that is cAMP-independent and involves protein kinase C. The study is of particular interest because regulation of melatonin biosynthesis in bovines may resemble that in primates more closely than that in rodents. [source] The newly synthesized linoleic acid derivative DCP-LA ameliorates memory deficits in animal models treated with amyloid-, peptide and scopolaminePSYCHOGERIATRICS, Issue 4 2005Tetsu NAGATA Abstract Background:, In our earlier study, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis -double bonds, facilitated hippocampal synaptic transmission by stimulating glutamate release from presynaptic terminals as mediated via ,7 acetylcholine (Ach) receptors under the influence of protein kinase C. The present study assessed the possibility of using DCP-LA as a cognitive enhancer in animal models. Methods:, Amyloid-,1,40 peptide (300 pM/day) or saline was continuously injected in the right lateral ventricle of rats for 2 weeks. Then, the water maze test was carried out, once per day for 7 days, 1 h after the intraperitoneal injection with DCP-LA or saline. In a different set of experiments, rats were intraperitoneally injected with scopolamine (1 mg/kg) and the water maze test was performed twice per day, with the first test taking place 1 h after the intraperitoneal injection with DCP-LA, galantamine or saline, and the second test starting 2 min after the end of the first. Results:, Continuous intraventricular injection with amyloid-,1,40 peptide in the rat lateral ventricle prolonged the latency for acquisition in the water maze test. DCP-LA (1 mg/kg, intraperitoneal (i.p.)) significantly improved the impairment, which reached a level similar to the latency for sham. Furthermore, DCP-LA (1 mg/kg, i.p.) significantly ameliorated learning and memory deficits in rats treated with scopolamine and was, if not more, effective than galantamine, a modest inhibitor of acetylcholinesterase with nicotinic ACh receptor modulation. Conclusion:, The results of the present study show that DCP-LA ameliorates learning and memory deficits induced by amyloid-,1,40 peptide or scopolamine. DCP-LA may thus offer new hope for dementia patients. [source] | |||||||||||||