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Selective Inactivation (selective + inactivation)
Selected AbstractsInactivation of phosphorylase is a major component of the mechanism by which insulin stimulates hepatic glycogen synthesisFEBS JOURNAL, Issue 13 2003Susan Aiston Multiple signalling pathways are involved in the mechanism by which insulin stimulates hepatic glycogen synthesis. In this study we used selective inhibitors of glycogen synthase kinase-3 (GSK-3) and an allosteric inhibitor of phosphorylase (CP-91149) that causes dephosphorylation of phosphorylase a, to determine the relative contributions of inactivation of GSK-3 and dephosphorylation of phosphorylase a as alternative pathways in the stimulation of glycogen synthesis by insulin in hepatocytes. GSK-3 inhibitors (SB-216763 and Li+) caused a greater activation of glycogen synthase than insulin (90% vs. 40%) but a smaller stimulation of glycogen synthesis (30% vs. 150%). The contribution of GSK-3 inactivation to insulin stimulation of glycogen synthesis was estimated to be less than 20%. Dephosphorylation of phosphorylase a with CP-91149 caused activation of glycogen synthase and translocation of the protein from a soluble to a particulate fraction and mimicked the stimulation of glycogen synthesis by insulin. The stimulation of glycogen synthesis by phosphorylase inactivation cannot be explained by either inhibition of glycogen degradation or activation of glycogen synthase alone and suggests an additional role for translocation of synthase. Titrations with the phosphorylase inactivator showed that stimulation of glycogen synthesis by insulin can be largely accounted for by inactivation of phosphorylase over a wide range of activities of phosphorylase a. We conclude that a signalling pathway involving dephosphorylation of phosphorylase a leading to both activation and translocation of glycogen synthase is a critical component of the mechanism by which insulin stimulates hepatic glycogen synthesis. Selective inactivation of phosphorylase can mimic insulin stimulation of hepatic glycogen synthesis. [source] Photolithographic Patterning of Ring-Opening Metathesis Catalysts on Silicon,ADVANCED MATERIALS, Issue 1 2005F. Harris Ruthenium-based metathesis catalysts have been successfully covalently bound to a thermal oxide layer on a Si(100) wafer. Selective inactivation of the catalyst is achieved via exposure to UV light using standard photolithographic techniques. Subsequent exposure of the wafer to a suitable monomer results in the formation of a patterned polymeric film that is covalently attached to the oxide layer (see Figure). [source] Postnatal maturation of GABAA and GABAC receptor function in the mammalian superior colliculusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2001Mathias Boller Abstract In the stratum griseum superficiale (SGS) of the mammalian superior colliculus, GABAC receptors seem to control the excitability of projection neurons by selective inactivation of local GABAergic interneurons. As the onset of visual responses to SC begins well after birth in the rat, it is possible to study developmental changes in GABAergic mechanisms that are linked to the onset of visual information processing. In order to analyse postnatal changes in inhibitory mechanisms that involve GABA receptor function, we used extracellular field potential (FP) recordings and single cell patch-clamp techniques in slices from postnatal day 4 (P4) to P32 and examined the effects of GABA and muscimol on electrically evoked SGS cell activity. While GABAA receptor activation affected FP amplitudes throughout postnatal development, GABAC receptor activation did not significantly change FP amplitudes until the third postnatal week. Results from patch-clamping single cells, however, clearly demonstrate that GABAC receptors are already functional at P4 , similar to GABAA receptors. Throughout postnatal development, activation of GABAC receptors leads to a strong inhibition of inhibitory postsynaptic activity, indicating that GABAC receptors are expressed by inhibitory interneurons. Furthermore, the proportion of neurons that show decreased excitatory postsynaptic activity during GABAC receptor activation correlates with the proportion of GABAergic interneurons in SGS. Our patch-clamp results indicate that the functional expression of GABAC receptors by GABAergic interneurons does not change significantly during postnatal development. However, our measurements of FP amplitudes indicate that the maturation of the efferent connections of these GABAergic neurons within SGS during the third postnatal week strongly changes GABAC receptor function. [source] Periodontitis as an infectious disease: specific features and their implicationsORAL DISEASES, Issue 2003A Mombelli Periodontitis may be viewed as an infectious disease with a number of specific characteristics. Pathogens of the subgingival microbiota can interact with host tissues even without direct tissue penetration. Hence, antimicrobial agents must be available at a sufficiently high concentration not only within the periodontal tissues, but also outside, in the environment of the periodontal pocket. The subgingival microbiota accumulate on the root surface to form an adherent layer of plaque with the characteristics of a biofilm. Several mechanisms, such as diffusion barriers, and selective inactivation of agents lead to an increased resistance of bacteria in biofilms. Mechanical supragingival plaque control is indispensable to prevent the re-emergence of periodontal pathogens and the re-establishment of a biofilm in treated sites. Since specific features have important implications for the use of antimicrobial agents in periodontal therapy, extrapolations from experiences made in the therapy of other infections are only partially valid. The ultimate evidence for the efficacy of systemic or local chemotherapy must be obtained from treatment studies in humans with adequate follow-up. [source] Intracellular distribution of peroxynitrite during doxorubicin cardiomyopathy: evidence for selective impairment of myofibrillar creatine kinaseBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2002Michael J Mihm Cardiac peroxynitrite and protein nitration are increased during doxorubicin cardiotoxicity, but the intracellular targets and functional consequences have not been defined. We investigated the intracellular distribution of protein nitration during doxorubicin cardiotoxicity in mice. Following in vivo cardiac function assessments by echocardiography, cardiac tissues were prepared for immunohistochemistry and electron microscopy 5 days after doxorubicin (20 mg kg,1) or vehicle control. Increased cardiac 3-nitrotyrosine was observed using light microscopy in doxorubicin treated animals. Immunogold electron microscopy (55,000×) revealed increased myofibrillar and mitochondrial 3-nitrotyrosine levels following doxorubicin, but cellular 3-nitrotyrosine density was 2 fold higher in myofibrils. We therefore investigated the actions of peroxynitrite on intact cardiac contractile apparatus. Skinned ventricular trabeculae were exposed to physiologically relevant peroxynitrite concentrations (50 or 300 nM) for 1 h, then Ca2+ induced contractile responses were measured in the presence of ATP (4 mM) or phosphocreatine (12 mM) as high energy phosphate supplier. ATP maximal force generation was unaltered after 50 nM peroxynitrite, but phosphocreatine/ATP response was reduced (0.99±0.63 vs 1.59±0.11), suggesting selective inactivation of myofibrillar creatine kinase (MM-CK). Reduction of ATP maximal force was observed at 300 nM peroxynitrite and phosphocreatine/ATP response was further reduced (0.64±0.30). Western blotting showed concentration dependent nitration of MM-CK in treated trabeculae. Similarly, cardiac tissues from doxorubicin treated mice demonstrated increased nitration and inactivation of MM-CK compared to controls. These results demonstrate that peroxynitrite-related protein nitration are mechanistic events in doxorubicin cardiomyopathy and that the cardiac myofibril is an important oxidative target in this setting. Furthermore, MM-CK may be a uniquely vulnerable target to peroxynitrite in vivo. British Journal of Pharmacology (2002) 135, 581,588; doi:10.1038/sj.bjp.0704495 [source] | ||||||||||