Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.
Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.
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DOI：
10.3390/ijms21218404
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发表时间：
2020-11-09
影响因子：
5.6
通讯作者：
Jones B
中科院分区：
文献类型：
--
作者：
Fang Z;Chen S;Manchanda Y;Bitsi S;Pickford P;David A;Shchepinova MM;Corrêa IR Jr;Hodson DJ;Broichhagen J;Tate EW;Reimann F;Salem V;Rutter GA;Tan T;Bloom SR;Tomas A;Jones B
胰高血糖素样肽-1受体（GLP-1 R）是血糖稳态的重要调节因子。GLP-1 R膜运输的配体特异性差异影响其信号传导特性和2型糖尿病的治疗潜力。在此，我们评价了不同因素如何结合联合收割机来控制GLP-1 R的内吞后转运至再循环与降解途径。在原代胰岛细胞、INS-1 832/3克隆β细胞和HEK 293细胞中进行实验，使用GLP-1 R的双正交标记，以确定GLP-1、毒蜥外泌肽-4和数种其他GLP-1 R激动剂肽处理后的定位和降解。我们还描述了一种罕见的GLP 1 R编码变体T149 M的作用，以及内体肽酶内皮素转换酶-1（ECE-1）在GLP 1 R转运中的作用。我们的数据揭示了GLP-1与exendin-4治疗如何与GLP-1 R优先靶向再循环途径相关。GLP-1（而非毒蜥外泌肽-4）是ECE-1的底物，并且由此产生的内体内降解倾向以及结合亲和力的差异有助于GLP-1 R运输行为和降解的改变。T149 M GLP-1 R变体显示信号传导和内化反应降低，这可能是由于与细胞内效应物偶联的细胞质区域破坏所致。这些观察结果提供了关于配体和基因型特异性因素如何影响GLP-1 R运输的见解。
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.
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影响因子：
5.6
作者：
Heydenreich FM;Vuckovic Z;Matkovic M;Veprintsev DB
通讯作者：
Veprintsev DB
影响因子：
7.3
作者：
Gupta, A.;Fujita, W.;Devi, L. A.
通讯作者：
Devi, L. A.
影响因子：
64.5
作者：
Hauser AS;Chavali S;Masuho I;Jahn LJ;Martemyanov KA;Gloriam DE;Babu MM
通讯作者：
Babu MM
影响因子：
--
作者：
Beinborn, M;Worrall, CI;Kopin, AS
通讯作者：
Kopin, AS
影响因子：
3.4
作者：
Ballesteros, JA;Deupi, X;Pardo, L
通讯作者：
Pardo, L