Order ID:89JHGSJE83839 | Style:APA/MLA/Harvard/Chicago | Pages:5-10 |
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Edited* by Robert J. Lefkowitz, Duke University Medical Center, The Howard Hughes Medical Institute, Durham, NC, and approved October 18, 2010 (received for review August 6, 2010) The activity of G protein-coupled receptors is regulated via hyperphosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M3-muscarinic receptor, a prototypical Gq/11-coupled receptor. This mutant mouse strain was used here to investigate the role of M3-muscarinic receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient receptor coupled to Gq/11-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as receptor internalization and ß-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M3-muscarinic receptors expressed on pancreatic islets regulate glucose homeostasis via receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of ß-arrestin to the phosphorylated M3-muscarinic receptor. In conclusion, our findings support the unique concept that M3-muscarinic receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/ arrestin-dependent coupling of the receptor to protein kinase D1. G-protein coupled receptor | ligand bias The vast majority of G protein-coupled receptors (GPCRs) respond to agonist occupation by becoming rapidly hyperphosphorylated within intracellular domains (1–3). This process not only leads to the uncoupling of the receptor from its cognate G proteins, but also allows for the activation of G proteinindependent signaling, a process that is driven largely by the recruitment of ß-arrestin adaptor proteins (4–7). As a consequence, GPCRs regulate an extensive array of signaling pathways and biological responses (3). G protein-independent signaling pathways have mostly been studied in recombinant systems. However, the current challenge is to understand to what extent these processes are involved in the regulation of key physiological responses. In the present study, we examined the in vivo role of GPCR phosphorylation by generating a knock-in mouse strain expressing a phosphorylation-deficient GPCR. Specifically, we used the M3- muscarinic acetylcholine receptor, a prototypic Gq/11-coupled GPCR, as a model system (8, 9). We and others have previously demonstrated that the M3-muscarinic receptor is rapidly phosphorylated on agonist occupation by a range of protein kinases that include members of the GPCR kinase (GRK) family, as well as casein kinase 1a and protein kinase CK2 (10–13). To define the potential physiological role of M3-muscarinic receptor phosphorylation, we generated a mouse strain where the wild-type M3- muscarinic receptor gene had been replaced by a phosphorylation
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Excellent Quality 95-100%
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Introduction
45-41 points The background and significance of the problem and a clear statement of the research purpose is provided. The search history is mentioned. |
Literature Support 91-84 points The background and significance of the problem and a clear statement of the research purpose is provided. The search history is mentioned. |
Methodology 58-53 points Content is well-organized with headings for each slide and bulleted lists to group related material as needed. Use of font, color, graphics, effects, etc. to enhance readability and presentation content is excellent. Length requirements of 10 slides/pages or less is met. |
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Average Score 50-85% |
40-38 points More depth/detail for the background and significance is needed, or the research detail is not clear. No search history information is provided. |
83-76 points Review of relevant theoretical literature is evident, but there is little integration of studies into concepts related to problem. Review is partially focused and organized. Supporting and opposing research are included. Summary of information presented is included. Conclusion may not contain a biblical integration. |
52-49 points Content is somewhat organized, but no structure is apparent. The use of font, color, graphics, effects, etc. is occasionally detracting to the presentation content. Length requirements may not be met. |
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Poor Quality 0-45% |
37-1 points The background and/or significance are missing. No search history information is provided. |
75-1 points Review of relevant theoretical literature is evident, but there is no integration of studies into concepts related to problem. Review is partially focused and organized. Supporting and opposing research are not included in the summary of information presented. Conclusion does not contain a biblical integration. |
48-1 points There is no clear or logical organizational structure. No logical sequence is apparent. The use of font, color, graphics, effects etc. is often detracting to the presentation content. Length requirements may not be met |
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