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GLP-1R signaling ne...
GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
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- Wright, Shane C. (author)
- Karolinska Institutet
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- Motso, Aikaterini (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
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- Koutsilieri, Stefania (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
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- Beusch, Christian M. (author)
- Karolinska Inst, Dept Med Biochem & Biophys, Chem 1, S-17177 Stockholm, Sweden.
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- Sabatier, Pierre (author)
- Uppsala universitet,Thoraxkirurgi,Karolinska Inst, Dept Med Biochem & Biophys, Chem 1, S-17177 Stockholm, Sweden.;Univ Copenhagen, Novo Nord Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
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- Berghella, Alessandro (author)
- Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark.;Univ Teramo, Fac Biosci & Agrofood & Environm Technol, I-64100 Teramo, Italy.
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- Blondel-Tepaz, Elodie (author)
- Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada.;Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ H3T 1J4, Canada.
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- Mangenot, Kimberley (author)
- Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada.;Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ H3T 1J4, Canada.
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- Pittarokoilis, Ioannis (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
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- Sismanoglou, Despoina-Christina (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
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- Le Gouill, Christian (author)
- Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada.
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- Olsen, Jesper V. (author)
- Univ Copenhagen, Novo Nord Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
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- Zubarev, Roman A. (author)
- Karolinska Institutet
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- Lambert, Nevin A. (author)
- Augusta Univ, Med Coll Georgia, Dept Pharmacol & Toxicol, Augusta, GA 30912 USA.
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- Hauser, Alexander S. (author)
- Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark.
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- Bouvier, Michel (author)
- Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada.
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- Lauschke, Volker M. (author)
- Karolinska Institutet
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Karolinska Institutet Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden (creator_code:org_t)
- Springer Nature, 2023
- 2023
- English.
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
- Related links:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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Abstract
Subject headings
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- G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences. Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor's signaling events and uncover associations between signaling profiles and adverse drug reactions.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Wright, Shane C.
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Motso, Aikaterin ...
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Koutsilieri, Ste ...
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Beusch, Christia ...
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Sabatier, Pierre
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Berghella, Aless ...
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show more...
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Blondel-Tepaz, E ...
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Mangenot, Kimber ...
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Pittarokoilis, I ...
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Sismanoglou, Des ...
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Le Gouill, Chris ...
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Olsen, Jesper V.
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Zubarev, Roman A ...
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Lambert, Nevin A ...
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Hauser, Alexande ...
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Bouvier, Michel
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Lauschke, Volker ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
- Articles in the publication
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Nature Communica ...
- By the university
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Uppsala University
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Karolinska Institutet