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1.
Muda M He C Martini PG Ferraro T Layfield S Taylor D Chevrier C Schweickhardt R Kelton C Ryan PL Bathgate RA 《Molecular human reproduction》2005,11(8):591-600
LGR7 and LGR8 are G protein-coupled receptors that belong to the leucine-rich repeat-containing G-protein coupled receptor (LGR) family, including the thyroid-stimulating hormone (TSH), LH and FSH receptors. LGR7 and LGR8 stimulate cAMP production upon binding of the cognate ligands, relaxin and insulin-like peptide 3 (INSL3), respectively. We cloned several novel splice variants of both LGR7 and LGR8 and analysed the function of four variants. LGR7.1 is a truncated receptor, including only the N-terminal region of the receptor and two leucine rich repeats. In contrast, LGR7.2, LGR7.10 and LGR 8.1 all contain an intact seven transmembrane domain and most of the extracellular region, lacking only one or two exons in the ectodomain. Our analysis demonstrates that although LGR7.10 and LGR8.1 are expressed at the cell surface, LGR7.2 is predominantly retained within cells and LGR7.1 is partially secreted. mRNA expression analysis revealed that several variants are co-expressed in various tissues. None of these variants were able to stimulate cAMP production following relaxin or INSL3 treatment. Unexpectedly, we did not detect any direct specific relaxin or INSL3 binding on any of the splice variants. The large number of receptor splice variants identified suggests an unforeseen complexity in the physiology of this novel hormone-receptor system. 相似文献
2.
Naotaka Tsutsumi Qianhui Qu Maša Mavri Maibritt S. Baggesen Shoji Maeda Deepa Waghray Christian Berg Brian K. Kobilka Mette M. Rosenkilde Georgios Skiniotis K. Christopher Garcia 《Immunity》2021,54(7):1405-1416.e7
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3.
Erik Slinger Ellen LangemeijerMarco Siderius Henry F. VischerMartine J. Smit 《Molecular and cellular endocrinology》2011
Viral G-protein-coupled receptors (vGPCRs) are chemokine receptor homologues encoded by the Herpes- and Capripoxviridae. They are thought to have been hijacked from the host genome during the course of evolution. These vGPCRs play different roles in the viral lifecycle and associated pathologies. Three members of the Herpesviridae, Kaposi sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) are capable of setting up persistent latent infections in humans. Two of the herpesviruses, KSHV and EBV, are associated with cancer, while HCMV may have an oncomodulary effect. 相似文献
4.
Vanessa M. Noriega Thomas J. Gardner Veronika Redmann Gerold Bongers Sergio A. Lira Domenico Tortorella 《Viruses》2014,6(3):1202-1218
Human cytomegalovirus (HCMV) encodes a number of viral proteins with homology to cellular G protein-coupled receptors (GPCRs). These viral GPCRs, including US27, US28, UL33, and UL78, have been ascribed numerous functions during infection, including activating diverse cellular pathways, binding to immunomodulatory chemokines, and impacting virus dissemination. To investigate the role of US28 during virus infection, two variants of the clinical isolate TB40/E were generated: TB40/E-US28YFP expressing a C-terminal yellow fluorescent protein tag, and TB40/E-FLAGYFP in which a FLAG-YFP cassette replaces the US28 coding region. The TB40/E-US28YFP protein localized as large perinuclear fluorescent structures at late times post-infection in fibroblasts, endothelial, and epithelial cells. Interestingly, US28YFP is a non-glycosylated membrane protein throughout the course of infection. US28 appears to impact cell-to-cell spread of virus, as the ΔUS28 virus (TB40/E-FLAGYFP) generated a log-greater yield of extracellular progeny whose spread could be significantly neutralized in fibroblasts. Most strikingly, in epithelial cells, where dissemination of virus occurs exclusively by the cell-to-cell route, TB40/E-FLAGYFP (ΔUS28) displayed a significant growth defect. The data demonstrates that HCMV US28 may contribute at a late stage of the viral life cycle to cell-to-cell dissemination of virus. 相似文献
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The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABAA receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world''s first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents. 相似文献
7.
Serving as one of our primary environmental inputs, vision is the most sophisticated sensory system in humans. Here, we present recent findings derived from energetics, genetics and physiology that provide a more advanced understanding of color perception in mammals. Energetics of cis–trans isomerization of 11-cis-retinal accounts for color perception in the narrow region of the electromagnetic spectrum and how human eyes can absorb light in the near infrared (IR) range. Structural homology models of visual pigments reveal complex interactions of the protein moieties with the light sensitive chromophore 11-cis-retinal and that certain color blinding mutations impair secondary structural elements of these G protein-coupled receptors (GPCRs). Finally, we identify unsolved critical aspects of color tuning that require future investigation. 相似文献
8.
《Pulmonary pharmacology & therapeutics》2014,27(2):164-169
BackgroundAsthma is characterized by chronic inflammation caused by activation of immune cells including Th2 lymphocytes and eosinophils. Phosphoinositide 3-kinase (PI3K) γ deficient asthmatic mice did not develop lung eosinophilia, although the detailed mechanisms are not well known. A CC chemokine eotaxin (CCL11) plays a prominent role in developing eosinophilic inflammation through CCR3. In this study, we tested the roles of PI3Kγ in eotaxin-induced eosinophil functions using a pharmacological inhibitor.MethodHuman peripheral blood eosinophils were isolated by CD16-negative selection method. The effect of AS605240, synthetic PI3Kγ inhibitor on eotaxin-induced adhesion, chemotaxis, and degranulation were studied using intracellular adhesion molecule-1 (ICAM-1)-coated plates, Boyden chamber system, ELISA for eosinophil-derived neurotoxin (EDN) levels in the culture supernatant, respectively. CCR3 expression levels and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were assessed by flowcytometry. Involvement of PI3Kγ in spontaneous apoptosis was studied using flowcytometry.ResultsAlthough AS605240 did not affect the eosinophil spontaneous apoptosis, eotaxin-induced chemotaxis, adhesion to ICAM-1 coated plate, and EDN release were inhibited by AS605240. AS605240 also inhibited the eotaxin-induced ERK1/2 phosphorylation without down-regulation of surface CCR3 expression.ConclusionThese results indicate that PI3Kγ inhibitor attenuates eotaxin-induced eosinophil functions by suppressing the downstream signaling of CCR3 without significant cytotoxicity. PI3Kγ plays an important role in the development of eosinophilic inflammation and blockade of PI3Kγ might be a therapeutic strategy for treatment of eosinophil-related diseases including asthma. 相似文献
9.
Tingfang Yi Bo Zhai Yonghao Yu Yoshikawa Kiyotsugu Thomas Raschle Manuel Etzkorn Hee-Chan Seo Michal Nagiec Rafael E. Luna Ellis L. Reinherz John Blenis Steven P. Gygi Gerhard Wagner 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(21):E2182-E2190
Breast cancer is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.7 million new cases and 522,000 deaths around the world in 2012 alone. Cancer stem cells (CSCs) are essential for tumor reoccurrence and metastasis which is the major source of cancer lethality. G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is critical for tumor metastasis. However, stromal cell-derived factor 1 (SDF-1)/CXCR4–mediated signaling pathways in breast CSCs are largely unknown. Using isotope reductive dimethylation and large-scale MS-based quantitative phosphoproteome analysis, we examined protein phosphorylation induced by SDF-1/CXCR4 signaling in breast CSCs. We quantified more than 11,000 phosphorylation sites in 2,500 phosphoproteins. Of these phosphosites, 87% were statistically unchanged in abundance in response to SDF-1/CXCR4 stimulation. In contrast, 545 phosphosites in 266 phosphoproteins were significantly increased, whereas 113 phosphosites in 74 phosphoproteins were significantly decreased. SDF-1/CXCR4 increases phosphorylation in 60 cell migration- and invasion-related proteins, of them 43 (>70%) phosphoproteins are unrecognized. In addition, SDF-1/CXCR4 upregulates the phosphorylation of 44 previously uncharacterized kinases, 8 phosphatases, and 1 endogenous phosphatase inhibitor. Using computational approaches, we performed system-based analyses examining SDF-1/CXCR4–mediated phosphoproteome, including construction of kinase–substrate network and feedback regulation loops downstream of SDF-1/CXCR4 signaling in breast CSCs. We identified a previously unidentified SDF-1/CXCR4-PKA-MAP2K2-ERK signaling pathway and demonstrated the feedback regulation on MEK, ERK1/2, δ-catenin, and PPP1Cα in SDF-1/CXCR4 signaling in breast CSCs. This study gives a system-wide view of phosphorylation events downstream of SDF-1/CXCR4 signaling in breast CSCs, providing a resource for the study of CSC-targeted cancer therapy.Breast cancer is the most common cancer in women, with an estimated 1.7 million new cases and 522,000 deaths around the world in 2012 alone. Tumor metastasis is the major source of cancer lethality. Cancer stem cells (CSCs) are small-percentage subpopulation within tumors, which are essential for tumor reoccurrence and metastasis (1). G protein-coupled receptor CXCR4 is critical for tumor growth and metastasis and plays important roles in CSC migration, invasion, and proliferation (2). Chemokine stromal cell-derived factor 1 (SDF-1) (CXCL-12) binds to chemokine (C-X-C motif) receptor 4 (CXCR4) and induces SDF-1/CXCR4 signaling. SDF-1 or CXCR4 knockout mice are embryonic lethal. SDF-1 and CXCR4 are vital for tumor angiogenesis and metastasis (3). The large-scale signal transduction and the feedback regulation downstream of SDF-1/CXCR4 signaling in breast CSCs are unknown but critical to understanding the cellular physiology of breast tumor regrowth and metastasis.Protein phosphorylation and dephosphorylation are essential for cellular signal processing (4). Dynamic regulation of reversible, site-specific protein phosphorylation is critical to the signaling networks that regulate CSC self-renewal, differentiation, and metastasis. Protein-reversible phosphorylation has been extensively analyzed in examining one or a few protein phosphorylation events that affect CSC signaling (1). However, the phosphoproteome composed by protein kinase-driven and phosphatase-regulated signaling networks largely controls CSC fate. Therefore, large-scale analysis of differentially regulated protein phosphorylation is central to understanding complex cellular events, such as CSC maintenance and dissemination.To unveil the signal transduction downstream of SDF-1/CXCR4 signaling in CSCs, in this study we have carried out isotope reductive dimethylation and large-scale liquid chromatography tandem mass spectrometry (LC-MS/MS)-based phosphoproteomic profiling and quantification in human breast CSCs upon SDF-1/CXCR4 stimulation. The phosphorylation events presented here include SDF-1/CXCR4–mediated phosphorylation sites in several key kinases and phosphatases, and several important signaling pathways in breast CSCs. 相似文献
10.
Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two ‘classical’ estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1−/−); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism. 相似文献