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971.
Sridharan M Bowles EA Richards JP Krantic M Davis KL Dietrich KA Stephenson AH Ellsworth ML Sprague RS 《American journal of physiology. Heart and circulatory physiology》2012,302(3):H553-H559
Erythrocytes have been implicated as controllers of vascular caliber by virtue of their ability to release the vasodilator ATP in response to local physiological and pharmacological stimuli. The regulated release of ATP from erythrocytes requires activation of a signaling pathway involving G proteins (G(i) or G(s)), adenylyl cyclase, protein kinase A, and the cystic fibrosis transmembrane conductance regulator as well as a final conduit through which this highly charged anion exits the cell. Although pannexin 1 has been shown to be the final conduit for ATP release from human erythrocytes in response to reduced oxygen tension, it does not participate in transport of ATP following stimulation of the prostacyclin (IP) receptor in these cells, which suggests that an additional protein must be involved. Using antibodies directed against voltage-dependent anion channel (VDAC)1, we confirm that this protein is present in human erythrocyte membranes. To address the role of VDAC in ATP release, two structurally dissimilar VDAC inhibitors, Bcl-x(L) BH4(4-23) and TRO19622, were used. In response to the IP receptor agonists, iloprost and UT-15C, ATP release was inhibited by both VDAC inhibitors although neither iloprost-induced cAMP accumulation nor total intracellular ATP concentration were altered. Together, these findings support the hypothesis that VDAC is the ATP conduit in the IP receptor-mediated signaling pathway in human erythrocytes. In addition, neither the pannexin inhibitor carbenoxolone nor Bcl-x(L) BH4(4-23) attenuated ATP release in response to incubation of erythrocytes with the β-adrenergic receptor agonist isoproterenol, suggesting the presence of yet another channel for ATP release from human erythrocytes. 相似文献
972.
G-protein-coupled receptors (GPCRs) are a large family of remarkably versatile membrane proteins that are attractive therapeutic targets because of their involvement in a vast range of normal physiological processes and pathological diseases. Upon activation, intracellular domains of GPCRs mediate signaling to G-proteins, but these domains have yet to be effectively exploited as drug targets. Cell-penetrating lipidated peptides called pepducins target specific intracellular loops of GPCRs and have recently emerged as effective allosteric modulators of GPCR activity. The lipid moiety facilitates translocation across the plasma membrane, where pepducins then specifically modulate signaling of their cognate receptor. To date, pepducins and related lipopeptides have been shown to specifically modulate the activity of diverse GPCRs and other membrane proteins, including protease-activated receptors (PAR1, PAR2, and PAR4), chemokine receptors (CXCR1, CXCR2, and CXCR4), sphingosine 1-phosphate receptor-3 (S1P3), the melanocortin-4 receptor, the Smoothened receptor, formyl peptide receptor-2 (FPR2), the relaxin receptor (LGR7), G-proteins (Gα(q/11/o/13)), muscarinic acetylcholine receptor and vanilloid (TRPV1) channels, and the GPIIb integrin. This minireview describes recent advances made using pepducin technology in targeting diverse GPCRs and the use of pepducins in identifying potential novel drug targets. 相似文献
973.
Jingxin Chen Katie L. Winarski Mike M. Myerburg Bruce R. Pitt Shaohu Sheng 《The Journal of biological chemistry》2012,287(42):35589-35598
Extracellular Zn2+ activates the epithelial Na+ channel (ENaC) by relieving Na+ self-inhibition. However, a biphasic Zn2+ dose response was observed, suggesting that Zn2+ has dual effects on the channel (i.e. activating and inhibitory). To investigate the structural basis for this biphasic effect of Zn2+, we examined the effects of mutating the 10 extracellular His residues of mouse γENaC. Four mutations within the finger subdomain (γH193A, γH200A, γH202A, and γH239A) significantly reduced the maximal Zn2+ activation of the channel. Whereas γH193A, γH200A, and γH202A reduced the apparent affinity of the Zn2+ activating site, γH239A diminished Na+ self-inhibition and thus concealed the activating effects of Zn2+. Mutation of a His residue within the palm subdomain (γH88A) abolished the low-affinity Zn2+ inhibitory effect. Based on structural homology with acid-sensing ion channel 1, γAsp516 was predicted to be in close proximity to γHis88. Ala substitution of the residue (γD516A) blunted the inhibitory effect of Zn2+. Our results suggest that external Zn2+ regulates ENaC activity by binding to multiple extracellular sites within the γ-subunit, including (i) a high-affinity stimulatory site within the finger subdomain involving His193, His200, and His202 and (ii) a low-affinity Zn2+ inhibitory site within the palm subdomain that includes His88 and Asp516. 相似文献
974.
Crawforth J Goodacre S Maxey R Bourrain S Patel S Marwood R O'Connor D Herbert R Hutson P Rowley M 《Bioorganic & medicinal chemistry letters》2000,10(24):2701-2703
A series of 3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.l]oct-3-yl)-2-phenyl-1H-indoles have been prepared and evaluated as ligands for the h5-HT2A receptor. 3-(8-Phenethyl-8-aza-bicyclo[3.2.l]oct-3-yI)-2-phenyl-1H-indole is a high-affinity (1.2 nM), selective (>800 fold over h5-HT2C and hD2 receptors) antagonist at the h5-HT2A receptor with oral bioavailability in rats. 相似文献
975.
Amssoms K Oza SL Augustyns K Yamani A Lambeir AM Bal G Van der Veken P Fairlamb AH Haemers A 《Bioorganic & medicinal chemistry letters》2002,12(19):2703-2705
Glutathionylspermidine synthetase (GspS) is an essential enzyme in the biosynthesis of trypanothione and is an attractive target for the design of selective anti-parasitic drugs. We synthesised a series of analogues of glutathione (L-gamma-Glu-L-Leu-X) where the glycine moiety has been substituted for other amino acids. These peptides were evaluated as substrates and inhibitors of GspS. Compounds with basic side chains such as diaminopropionic acid were found to be good inhibitors (K(i): 7.2 microM). Substitution of the glycine part abolished the GspS substrate properties of the tripeptide. 相似文献
976.
Background
ROCK1 and ROCK2 are serine/threonine kinases that function downstream of the small GTP-binding protein RhoA. Rho signalling via ROCK regulates a number of cellular functions including organisation of the actin cytoskeleton, cell adhesion and cell migration.Methodology/Principal Findings
In this study we use RNAi to specifically knockdown ROCK1 and ROCK2 and analyse their role in assembly of adhesion complexes in human epidermal keratinocytes. We observe that loss of ROCK1 inhibits signalling via focal adhesion kinase resulting in a failure of immature adhesion complexes to form mature stable focal adhesions. In contrast, loss of ROCK2 expression results in a significant reduction in adhesion complex turnover leading to formation of large, stable focal adhesions. Interestingly, loss of either ROCK1 or ROCK2 expression significantly impairs cell migration indicating both ROCK isoforms are required for normal keratinocyte migration.Conclusions
ROCK1 and ROCK2 have distinct and separate roles in adhesion complex assembly and turnover in human epidermal keratinocytes. 相似文献977.
Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA) behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis) and six selected F1 hybrids. All rats were trained to press a lever to obtain food starting on postnatal day (PN) 32, and then nicotine (0.03 mg/kg/infusion, i.v.) reinforcement was made available on PN41-42 (10 consecutive daily 2 h sessions). Of the 12 isogenic strains, Fisher rats self-administered the fewest nicotine infusions (1.45±0.36/d) during the last 3 d, while Lewis rats took the most nicotine (13.0±1.4/d). These strains sorted into high, intermediate and low self-administration groups in 2, 2, and 8 strains, respectively. The influence of heredity on nicotine SA (0.64) is similar to that reported for humans. Therefore, this panel of isogenic rat strains effectively models the overall impact of genetics on the vulnerability to acquire nicotine-reinforced behavior during adolescence. Separate groups of rats responded for food starting on PN41. The correlation between nicotine and food reward was not significant. Hence, the genetic control of the motivation to obtain nicotine is distinctly different from food reward, indicating the specificity of the underlying genetic mechanisms. Lastly, the behavior of F1 hybrids was not predicted from the additive behavior of the parental strains, indicating the impact of significant gene-gene interactions on the susceptibility to nicotine reward. Taken together, the behavioral characteristics of this model indicate its strong potential to identify specific genes mediating the human vulnerability to smoke cigarettes. 相似文献
978.
Selfish DNA poses a significant challenge to genome stability and organismal fitness in diverse eukaryotic lineages. Although selfish mitochondrial DNA (mtDNA) has known associations with cytoplasmic male sterility in numerous gynodioecious plant species and is manifested as petite mutants in experimental yeast lab populations, examples of selfish mtDNA in animals are less common. We analyzed the inheritance and evolution of mitochondrial DNA bearing large heteroplasmic deletions including nad5 gene sequences (nad5Δ mtDNA), in the nematode Caenorhabditis briggsae. The deletion is widespread in C. briggsae natural populations and is associated with deleterious organismal effects. We studied the inheritance patterns of nad5Δ mtDNA using eight sets of C. briggsae mutation-accumulation (MA) lines, each initiated from a different natural strain progenitor and bottlenecked as single hermaphrodites across generations. We observed a consistent and strong drive toward higher levels of deletion-bearing molecules in the heteroplasmic pool of mtDNA after ten generations of bottlenecking. Our results demonstrate a uniform transmission bias whereby nad5Δ mtDNA accumulates to higher levels relative to intact mtDNA in multiple genetically diverse natural strains of C. briggsae. We calculated an average 1% per-generation transmission bias for deletion-bearing mtDNA relative to intact genomes. Our study, coupled with known deleterious phenotypes associated with high deletion levels, shows that nad5Δ mtDNA are selfish genetic elements that have evolved in natural populations of C. briggsae, offering a powerful new system to study selfish mtDNA dynamics in metazoans. 相似文献
979.
Steven John Kiddle Madhav Thambisetty Andrew Simmons Joanna Riddoch-Contreras Abdul Hye Eric Westman Ian Pike Malcolm Ward Caroline Johnston Michelle Katharine Lupton Katie Lunnon Hilkka Soininen Iwona Kloszewska Magda Tsolaki Bruno Vellas Patrizia Mecocci Simon Lovestone Stephen Newhouse Richard Dobson for the Alzheimers Disease Neuroimaging Initiative 《PloS one》2012,7(9)
Changes in brain amyloid burden have been shown to relate to Alzheimer''s disease pathology, and are believed to precede the development of cognitive decline. There is thus a need for inexpensive and non-invasive screening methods that are able to accurately estimate brain amyloid burden as a marker of Alzheimer''s disease. One potential method would involve using demographic information and measurements on plasma samples to establish biomarkers of brain amyloid burden; in this study data from the Alzheimer''s Disease Neuroimaging Initiative was used to explore this possibility. Sixteen of the analytes on the Rules Based Medicine Human Discovery Multi-Analyte Profile 1.0 panel were found to associate with [11C]-PiB PET measurements. Some of these markers of brain amyloid burden were also found to associate with other AD related phenotypes. Thirteen of these markers of brain amyloid burden – c-peptide, fibrinogen, alpha-1-antitrypsin, pancreatic polypeptide, complement C3, vitronectin, cortisol, AXL receptor kinase, interleukin-3, interleukin-13, matrix metalloproteinase-9 total, apolipoprotein E and immunoglobulin E – were used along with co-variates in multiple linear regression, and were shown by cross-validation to explain >30% of the variance of brain amyloid burden. When a threshold was used to classify subjects as PiB positive, the regression model was found to predict actual PiB positive individuals with a sensitivity of 0.918 and a specificity of 0.545. The number of APOE ϵ 4 alleles and plasma apolipoprotein E level were found to contribute most to this model, and the relationship between these variables and brain amyloid burden was explored. 相似文献
980.
Choong-Ki Kim Jodie E. Toft Michael Papenfus Gregory Verutes Anne D. Guerry Marry H. Ruckelshaus Katie K. Arkema Gregory Guannel Spencer A. Wood Joanna R. Bernhardt Heather Tallis Mark L. Plummer Benjamin S. Halpern Malin L. Pinsky Michael W. Beck Francis Chan Kai M. A. Chan Phil S. Levin Stephen Polasky 《PloS one》2012,7(11)
Many hope that ocean waves will be a source for clean, safe, reliable and affordable energy, yet wave energy conversion facilities may affect marine ecosystems through a variety of mechanisms, including competition with other human uses. We developed a decision-support tool to assist siting wave energy facilities, which allows the user to balance the need for profitability of the facilities with the need to minimize conflicts with other ocean uses. Our wave energy model quantifies harvestable wave energy and evaluates the net present value (NPV) of a wave energy facility based on a capital investment analysis. The model has a flexible framework and can be easily applied to wave energy projects at local, regional, and global scales. We applied the model and compatibility analysis on the west coast of Vancouver Island, British Columbia, Canada to provide information for ongoing marine spatial planning, including potential wave energy projects. In particular, we conducted a spatial overlap analysis with a variety of existing uses and ecological characteristics, and a quantitative compatibility analysis with commercial fisheries data. We found that wave power and harvestable wave energy gradually increase offshore as wave conditions intensify. However, areas with high economic potential for wave energy facilities were closer to cable landing points because of the cost of bringing energy ashore and thus in nearshore areas that support a number of different human uses. We show that the maximum combined economic benefit from wave energy and other uses is likely to be realized if wave energy facilities are sited in areas that maximize wave energy NPV and minimize conflict with existing ocean uses. Our tools will help decision-makers explore alternative locations for wave energy facilities by mapping expected wave energy NPV and helping to identify sites that provide maximal returns yet avoid spatial competition with existing ocean uses. 相似文献