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541.
Daniel P. Poole Silvia Amadesi Nicholas A. Veldhuis Fe C. Abogadie TinaMarie Lieu William Darby Wolfgang Liedtke Michael J. Lew Peter McIntyre Nigel W. Bunnett 《The Journal of biological chemistry》2013,288(8):5790-5802
G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain. We investigated the signaling mechanisms by which PAR2 regulates TRPV4 and determined the importance of tyrosine phosphorylation in this process. Human TRPV4 was expressed in HEK293 cells under control of a tetracycline-inducible promoter, allowing controlled and graded channel expression. In cells lacking TRPV4, the PAR2 agonist stimulated a transient increase in [Ca2+]i. TRPV4 expression led to a markedly sustained increase in [Ca2+]i. Removal of extracellular Ca2+ and treatment with the TRPV4 antagonists Ruthenium Red or HC067047 prevented the sustained response. Inhibitors of phospholipase A2 and cytochrome P450 epoxygenase attenuated the sustained response, suggesting that PAR2 generates arachidonic acid-derived lipid mediators, such as 5′,6′-EET, that activate TRPV4. Src inhibitor 1 suppressed PAR2-induced activation of TRPV4, indicating the importance of tyrosine phosphorylation. The TRPV4 tyrosine mutants Y110F, Y805F, and Y110F/Y805F were expressed normally at the cell surface. However, PAR2 was unable to activate TRPV4 with the Y110F mutation. TRPV4 antagonism suppressed PAR2 signaling to primary nociceptive neurons, and TRPV4 deletion attenuated PAR2-stimulated neurogenic inflammation. Thus, PAR2 activation generates a signal that induces sustained activation of TRPV4, which requires a key tyrosine residue (TRPV4-Tyr-110). This mechanism partly mediates the proinflammatory actions of PAR2. 相似文献
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Ming Gao Guijie Guo Jinzhou Huang Xiaonan Hou Hyoungjun Ham Wootae Kim Fei Zhao Xinyi Tu Qin Zhou Chao Zhang Qian Zhu Jiaqi Liu Yuanliang Yan Zhijie Xu Ping Yin Kuntian Luo John Weroha Min Deng Daniel D Billadeau Zhenkun Lou 《Nucleic acids research》2021,49(6):3322
RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer. 相似文献
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Yayue Liu Xinyi Xue Longjian Zhou Wencong Yang Zhigang She Qingnan Liao Yunkai Feng Xiaokun Chen Yi Zhang 《化学与生物多样性》2023,20(8):e202300735
Acetylcholinesterase (AChE) inhibitory activity-guided studies on the mangrove-derived endophytic fungus Penicillium citrinum YX-002 led to the isolation of nine secondary metabolites, including one new quinolinone derivative, quinolactone A ( 1 ), a pair of epimers quinolactacin C1 ( 2 ) and 3-epi-quinolactacin C1 ( 3 ), together with six known analogs ( 4 – 9 ). Their structures were elucidated based on extensive mass spectrometry (MS) and 1D/2D nuclear magnetic resonance (NMR) spectroscopic analyses, and compared with data in the literature. The absolute configurations of compounds 1 – 3 was determined by combination of electronic circular dichroism (ECD) calculations and X-Ray single crystal diffraction technique using CuKα radiation. In bioassays, compounds 1 , 4 and 7 showed moderate AChE inhibitory activities with IC50 values of 27.6, 19.4 and 11.2 μmol/L, respectively. The structure-activity relationships (SARs) analysis suggested that the existence of carbonyl group on C-3 and the oxygen atom on the five-membered ring were beneficial to the activity. Molecular docking results showed that compound 7 had a lower affinity interaction energy (−9.3 kcal/mol) with stronger interactions with different sites in AChE activities, which explained its higher activities. 相似文献
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讨论具有性质(V)的广义Lyapunov函数的确定与判别,从而基本上完成利用广义Lyapunov函数研究微分系统关于两种量度的相对稳定性问题. 相似文献
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