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91.
The melanocortin receptor accessory protein 2 (MRAP2) is essential for several physiological functions of the ghrelin receptor growth hormone secretagogue receptor 1a (GHSR1a), including increasing appetite and suppressing insulin secretion. In the absence of MRAP2, GHSR1a displays high constitutive activity and a weak G-protein–mediated response to ghrelin and readily recruits β-arrestin. In the presence of MRAP2, however, G-protein–mediated signaling via GHSR1a is strongly dependent on ghrelin stimulation and the recruitment of β-arrestin is significantly diminished. To better understand how MRAP2 modifies GHSR1a signaling, here we investigated the role of several phosphorylation sites within the C-terminal tail and third intracellular loop of GHSR1a, as well as the mechanism behind MRAP2-mediated inhibition of β-arrestin recruitment. We show that Ser252 and Thr261 in the third intracellular loop of GHSR1a contribute to β-arrestin recruitment, whereas the C-terminal region is not essential for β-arrestin interaction. Additionally, we found that MRAP2 inhibits GHSR1a phosphorylation by blocking the interaction of GRK2 and PKC with the receptor. Taken together, these data suggest that MRAP2 alters GHSR1a signaling by directly impacting the phosphorylation state of the receptor and that the C-terminal tail of GHSR1a prevents rather than contribute to β-arrestin recruitment.The “hunger hormone” ghrelin is secreted by X/A cells of the oxyntic mucosa of the stomach in response to a low energetic state, which leads to an increase in appetite (1, 2) and prevents hypoglycemia (3, 4). Ghrelin is the agonist of the growth hormone secretagogue receptor 1a (GHSR1a), a G-protein–coupled receptor (GPCR) expressed in the brain and in multiple peripheral organs including the heart and the endocrine pancreas. Activation of GHSR1a by ghrelin in hypothalamic agouti-related protein (AgRP) neurons potently stimulates feeding (5, 6, 7). In pituitary somatotrophs, GHSR1a stimulation promotes growth hormone release (8, 9, 10). Finally, in cardiomyocytes, ghrelin increases cell survival and contractility (11, 12) while in the endocrine pancreas the hormone inhibits insulin secretion (13, 14).GHSR1a primarily couples to Gαq/11, thus stimulating the production of intracellular inositol triphosphate (IP) 3. Like other GPCRs, agonist stimulation results in phosphorylation of GHSR1a by kinases, including GPCR kinase 2 (GRK2) and PKC (15), and β-arrestin recruitment. Notably, GHSR1a contains several phosphorylation sites within the C-terminal tail, some of which have been shown to be important for β-arrestin recruitment (16). However, although other putative phosphorylation sites are present in the third intracellular loop (ICL3) of GHSR1a, their role in β-arrestin recruitment has not yet been described.When expressed in heterologous cells, GHSR1a displays a high constitutive activity and a limited ghrelin-stimulated responses (17).Both constitutive- and agonist-stimulated GHSR1a signaling are regulated by the single transmembrane melanocortin receptor accessory protein 2 (MRAP2), which functions to drastically reduce GHSR1a constitutive activity and increase ghrelin-stimulated responses (17). Additionally, MRAP2 significantly inhibits ghrelin-induced β-arrestin recruitment to GHSR1a (17). As such, MRAP2 is essential for several physiological functions of ghrelin including its orexigenic activity (18) and its insulinostatic actions (14). Global or AGRP neuron–targeted deletion of MRAP2 abrogates the effect of ghrelin on food intake (18) and global or pancreatic δ-cell-targeted deletion of MRAP2 prevents ghrelin-mediated inhibition of insulin secretion (14).Although expressed in AGRP neurons and pancreatic δ-cells (thus promoting G-protein coupling and inhibiting β-arrestin-dependent signaling), MRAP2 is not present in every GHSR1a-expressing tissue. Consequently, it is possible that β-arrestin signaling plays an important role in the physiological function of ghrelin in tissues where MRAP2 is absent. Whereas, the inhibition of β-arrestin recruitment to GHSR1a by MRAP2 is well established and the domains of MRAP2 required for this function have been identified (17), the molecular mechanism by which MRAP2 alters GHSR1a signaling is not yet understood. In this study, we investigated the importance of GHSR1a phosphorylation for β-arrestin recruitment and the mechanism involved in MRAP2-mediated inhibition of β-arrestin recruitment. 相似文献
92.
93.
Amplification of a novel gene, sanA, abolishes a vancomycin-sensitive defect in Escherichia coli.
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We have isolated an Escherichia coli gene which, when overexpressed, is able to complement the permeability defects of a vancomycin-susceptible mutant. This gene, designated sanA, is located at min 47 of the E. coli chromosome and codes for a 20-kDa protein with a highly hydrophobic amino-terminal segment. A strain carrying a null mutation of the sanA gene, transferred to the E. coli chromosome by homologous recombination, is perfectly viable, but after two generations at high temperature (43 degrees C), the barrier function of its envelope towards vancomycin is defective. 相似文献
94.
Interaction of adriamycin with DNA as studied by resonance Raman spectroscopy. 总被引:4,自引:3,他引:1
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M Manfait A J Alix P Jeannesson J C Jardillier T Theophanides 《Nucleic acids research》1982,10(12):3803-3816
Raman and resonance Raman spectra of the complex DNA-adriamycin in aqueous solution have been recorded and analysed. Calf thymus DNA was used and it is found that in the complex DNA-adriamycin the chromophore of adriamycin is intercalated in the GC sequences. The substituents on the rings give hydrogen bonding interactions with the base pairs above and below the intercalation site. It is suggested from the Raman and resonance Raman spectral modifications that the phenolic groups of the chromophore are involved in the drug-DNA intercalation, in addition to pi-pi, hydroxyl and amino group interactions. 相似文献
95.
L. Debelle S. M. Wei M. P. Jacob W. Hornebeck A. J. P. Alix 《European biophysics journal : EBJ》1992,21(5):321-329
Secondary structure and antigenicity predictive methods have been applied to the sequences of human and bovine tropoelastins in order to have some insight into the molecular structure of its insoluble counterpart, i.e., elastin. For both tropoelastins, all the predictions yielded 11 major regions, in which the pleated conformation was predominant, separated by 10 strong helical segments of various lengths located within alanyl rich regions of the chains. The overall conformations of human and bovine tropoelastins were estimated to contain 18 ± 5% -helices, 63 ± 17% -sheets, 13 ± 13% -turns and 6 ± 6% random coil. For both tropoelastins, antigenicity predictions indicated the presence of seven synthetic decapeptides corresponding to continuous linear epitopes of the molecule. Some of the predicted epitopes are located in the same regions in both species while others are not. These predictions have allowed us to propose an / conformation for tropoelastin. Therefore this extracellular matrix macromolecule might be more structured (10 helical segments for about 18% of the overall structure) than previously suggested.Abbreviations HTPE
human tropoelastin
- BTPE
bovine tropoelastin
- AG
antigenic index
- CF
Chou and Fasman algorithm
- GOR
method of Garnier Osguthorpe and Robson
- DC
decision constant
- CD
circular dichroism
- NMR
nuclear magnetic resonance 相似文献
96.
Ashare A Powers LS Butler NS Doerschug KC Monick MM Hunninghake GW 《American journal of physiology. Lung cellular and molecular physiology》2005,288(4):L633-L640
Using a murine model of sepsis, we found that the balance of tissue pro- to anti-inflammatory cytokines directly correlated with severity of infection and mortality. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Liver tissue was analyzed for levels of IL-1beta, IL-1 receptor antagonist (IL-1ra), tumor necrosis factor (TNF)-alpha, and soluble TNF receptor 1 by ELISA. Bacterial DNA was measured using quantitative real-time PCR. After CLP, early predominance of proinflammatory cytokines (6 h) transitioned to anti-inflammatory predominance at 24 h. The elevated anti-inflammatory cytokines were mirrored by increased tissue bacterial levels. The degree of anti-inflammatory response compared with proinflammatory response correlated with the bacterial concentration. To modulate the timing of the anti-inflammatory response, mice were treated with IL-1ra before CLP. This resulted in decreased proinflammatory cytokines, earlier bacterial load, and increased mortality. These studies show that the initial tissue proinflammatory response to sepsis is followed by an anti-inflammatory response. The anti-inflammatory phase is associated with increased bacterial load and mortality. These data suggest that it is the timing and magnitude of the anti-inflammatory response that predicts severity of infection in a murine model of sepsis. 相似文献
97.
Pathway-specific profiling identifies the NF-kappa B-dependent tumor necrosis factor alpha-regulated genes in epidermal keratinocytes 总被引:5,自引:0,他引:5
Identification of tumor necrosis factor alpha (TNF alpha) as the key agent in inflammatory disorders led to new therapies specifically targeting TNF alpha and avoiding many side effects of earlier anti-inflammatory drugs. However, because of the wide spectrum of systems affected by TNF alpha, drugs targeting TNF alpha have a potential risk of delaying wound healing, secondary infections, and cancer. Indeed, increased risks of tuberculosis and carcinogenesis have been reported as side effects after anti-TNF alpha therapy. TNF alpha regulates many processes (e.g. immune response, cell cycle, and apoptosis) through several signal transduction pathways that convey the TNF alpha signals to the nucleus. Hypothesizing that specific TNF alpha-dependent pathways control specific processes and that inhibition of a specific pathway may yield even more precisely targeted therapies, we used oligonucleotide microarrays and parthenolide, an NF-kappa B-specific inhibitor, to identify the NF-kappa B-dependent set of the TNF alpha-regulated genes in human epidermal keratinocytes. Expression of approximately 40% of all TNF alpha-regulated genes depends on NF-kappa B; 17% are regulated early (1-4 h post-treatment), and 23% are regulated late (24-48 h). Cytokines and apoptosis-related and cornification proteins belong to the "early" NF-kappa B-dependent group, and antigen presentation proteins belong to the "late" group, whereas most cell cycle, RNA-processing, and metabolic enzymes are not NF-kappa B-dependent. Therefore, inflammation, immunomodulation, apoptosis, and differentiation are on the NF-kappa B pathway, and cell cycle, metabolism, and RNA processing are not. Most early genes contain consensus NF-kappaB binding sites in their promoter DNA and are, presumably, directly regulated by NF-kappa B, except, curiously, the cornification markers. Using siRNA silencing, we identified cFLIP/CFLAR as an essential NF-kappa B-dependent antiapoptotic gene. The results confirm our hypothesis, suggesting that inhibiting a specific TNF alpha-dependent signaling pathway may inhibit a specific TNF alpha-regulated process, leaving others unaffected. This could lead to more specific anti-inflammatory agents that are both more effective and safer. 相似文献
98.
Escherichia coli DnaK and rat Hsc70 are members of the highly conserved 70-kDa heat shock protein (Hsp70) family that show strong sequence and structure similarities and comparable functional properties in terms of interactions with peptides and unfolded proteins and cooperation with cochaperones. We show here that, while the DnaK protein is, as expected, able to complement an E. coli dnaK mutant strain for growth at high temperatures and lambda phage propagation, Hsc70 protein is not. However, an Hsc70 in which the peptide-binding domain has been replaced by that of DnaK is able to complement this strain for both phenotypes, suggesting that the peptide-binding domain of DnaK is essential to fulfill the specific functions of this protein necessary for growth at high temperatures and for lambda phage replication. The implications of these findings on the functional specificities of the Hsp70s and the role of protein-protein interactions in the DnaK chaperone system are discussed. 相似文献
99.
100.