GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics.
GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics.
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DOI：
10.1038/s41467-023-41893-4
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发表时间：
2023-10-09
影响因子：
16.6
通讯作者：
Lauschke, Volker M.
中科院分区：
文献类型：
--
作者：
Wright, Shane C.;Motso, Aikaterini;Koutsilieri, Stefania;Beusch, Christian M.;Sabatier, Pierre;Berghella, Alessandro;Blondel-Tepaz, Elodie;Mangenot, Kimberley;Pittarokoilis, Ioannis;Sismanoglou, Despoina-Christina;Le Gouill, Christian;Olsen, Jesper V.;Zubarev, Roman A.;Lambert, Nevin A.;Hauser, Alexander S.;Bouvier, Michel;Lauschke, Volker M.
G蛋白偶联受体是重要的药物靶点，参与并激活多个细胞间的信号转导。从与不良事件相关的信号中区分治疗信号是迈向合理药物设计的重要一步。高血糖素样多肽-1受体(GLP-1R)是治疗糖尿病和肥胖症的有效靶点，但针对该受体的药物经常导致不良反应。利用最近开发的生物传感器，我们探索了GLP-1R在4个细胞区段激活15条通路的能力，并证明了旨在提高GLP-1R激动剂治疗潜力的修饰以途径和区段选择性的方式极大地影响化合物的疗效、效力和安全性。这些发现结合比较结构分析、时间推移显微镜和磷酸蛋白质组学，揭示了GLP-1R激动剂在受体构象、功能选择性和位置偏向水平上的独特信号特征，从而将信号邻域与功能不同的细胞结果和临床后果联系在一起。胰升糖素样肽-1受体的激动剂用于治疗糖尿病和肥胖症。在这里，赖特等人。调查受体信号事件的亚细胞位置，并发现信号特征与药物不良反应之间的关联。
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.
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影响因子：
7.3
作者：
Chandan, Naincy R.;Abraham, Saji;SenGupta, Shuvasree;Parent, Carole A.;Smrcka, Alan, V
通讯作者：
Smrcka, Alan, V
影响因子：
64.8
作者：
Jazayeri, Ali;Rappas, Mathieu;Marshall, Fiona H.
通讯作者：
Marshall, Fiona H.
DOI：
10.1073/pnas.220413597
发表时间：
2000-10-24
影响因子：
11.1
作者：
Fang, XJ;Yu, SX;Mills, GB
通讯作者：
Mills, GB
影响因子：
1.1
作者：
Huang, Lan;Zalkikar, Jyoti;Tiwari, Ram C.
通讯作者：
Tiwari, Ram C.
影响因子：
16.6
作者：
Klein Herenbrink C;Sykes DA;Donthamsetti P;Canals M;Coudrat T;Shonberg J;Scammells PJ;Capuano B;Sexton PM;Charlton SJ;Javitch JA;Christopoulos A;Lane JR
通讯作者：
Lane JR