Targeting GLP-1 receptor trafficking to improve agonist efficacy.
Targeting GLP-1 receptor trafficking to improve agonist efficacy.
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DOI：
10.1038/s41467-018-03941-2
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发表时间：
2018-04-23
影响因子：
16.6
通讯作者：
Bloom SR
中科院分区：
文献类型：
--
作者：
Jones B;Buenaventura T;Kanda N;Chabosseau P;Owen BM;Scott R;Goldin R;Angkathunyakul N;Corrêa IR Jr;Bosco D;Johnson PR;Piemonti L;Marchetti P;Shapiro AMJ;Cochran BJ;Hanyaloglu AC;Inoue A;Tan T;Rutter GA;Tomas A;Bloom SR
胰高血糖素样肽-1受体（GLP-1 R）激活可促进胰腺β细胞分泌胰岛素，导致体重减轻，是2型糖尿病（T2 D）的重要药理学靶点。与其他G蛋白偶联受体一样，GLP-1 R经历激动剂介导的内吞作用，但调节GLP-1 R内吞转运的功能和治疗后果尚未明确定义。在这里，我们研究了一系列偏向性GLP-1 R激动剂，其GLP-1 R内化和再循环倾向不同。与一组FDA批准的GLP-1模拟物相比，将GLP-1 R保留在质膜上的化合物产生更大的长期胰岛素释放，这取决于β-抑制蛋白募集的减少和更快的激动剂解离速率。这些分子在小鼠中引起血糖益处，而不伴随恶心体征的增加，这是GLP-1治疗的常见副作用。我们的研究确定了一组具有特定GLP-1 R转运特征的药物，以及作为T2 D治疗的更高疗效和耐受性的潜力。胰高血糖素样肽-1受体（GLP-1 R）促进胰腺β细胞分泌胰岛素，并经历激动剂介导的内吞作用。在此，作者研究了由不同激动剂引起的GLP-1 R内吞作用，并表明GLP-1 R的质膜保留时间较长，导致长期胰岛素释放增加。
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments. Glucagon-like peptide-1 receptor (GLP-1R) promotes insulin secretion from pancreatic beta cells and undergoes agonist-mediated endocytosis. Here, authors study GLP-1R endocytosis caused by different agonists and show that a longer plasma membrane retention time of GLP-1R results in greater long-term insulin release.
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影响因子：
25.7
作者：
Armstrong MJ;Hull D;Guo K;Barton D;Hazlehurst JM;Gathercole LL;Nasiri M;Yu J;Gough SC;Newsome PN;Tomlinson JW
通讯作者：
Tomlinson JW
影响因子：
29
作者：
Balland E;Dam J;Langlet F;Caron E;Steculorum S;Messina A;Rasika S;Falluel-Morel A;Anouar Y;Dehouck B;Trinquet E;Jockers R;Bouret SG;Prévot V
通讯作者：
Prévot V
影响因子：
64.8
作者：
Goodman, OB;Krupnick, JG;Benovic, JL
通讯作者：
Benovic, JL
影响因子：
5.8
作者：
Barrington, P.;Chien, J. Y.;Hardy, T. A.
通讯作者：
Hardy, T. A.
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