Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).
Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).
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DOI：
10.1074/jbc.m114.624601
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发表时间：
2015-09-18
期刊：
影响因子：
--
通讯作者：
Ladds G
中科院分区：
文献类型：
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作者：
Weston C;Lu J;Li N;Barkan K;Richards GO;Roberts DJ;Skerry TM;Poyner D;Pardamwar M;Reynolds CA;Dowell SJ;Willars GB;Ladds G
背景：胰高血糖素和胰高血糖素样肽-1（GLP-1）受体是治疗2型糖尿病的重要靶点。结果：我们描述了新的胰高血糖素受体药理学，通过与受体活性修饰蛋白-2（RAMP 2）的相互作用。结论：RAMP 2调节胰高血糖素受体的配体结合和G蛋白选择性。意义：在设计抗糖尿病治疗时应考虑RAMP 2的作用。胰高血糖素和胰高血糖素样肽-1（GLP-1）受体在调节血糖水平中发挥重要的相反作用。因此，这些受体已被确定为新型糖尿病治疗的靶点。然而，作用于GLP-1受体的药物尽管具有临床疗效，但与严重的不良副作用相关，并且胰高血糖素受体的靶向尚未成功。在这里，我们使用酵母报告基因测定和哺乳动物系统的组合，以提供胰高血糖素受体信号转导的更完整的理解，考虑到多种配体的作用，与受体相互作用蛋白受体活性修饰蛋白2（RAMP 2）的关联，以及单个G蛋白α亚基的作用。我们证明RAMP 2改变胰高血糖素受体的配体选择性和G蛋白偏好。重要的是，我们还发现了治疗用GLP-1受体配体在胰高血糖素受体上的新交叉反应性，该交叉反应性被RAMP 2相互作用消除。这项研究揭示了胰高血糖素受体作为GLP-1受体激动剂的一个先前未鉴定的靶点，并强调了RAMP 2在调节其药理学中的作用。RAMPs的这种以前未被认识的功能突出了在未来药物开发中考虑所有受体相互作用蛋白的必要性。
Background: The glucagon and glucagon-like peptide-1 (GLP-1) receptors are important targets for treating type 2 diabetes. Results: We describe novel glucagon receptor pharmacology, through interaction with the receptor activity-modifying protein-2 (RAMP2). Conclusion: RAMP2 regulates both ligand binding and G protein selectivity of the glucagon receptor. Significance: The effect of RAMP2 should be considered when designing anti-diabetic treatments. The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, have been associated with severe adverse side-effects, and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems to provide a more complete understanding of glucagon receptor signaling, considering the effect of multiple ligands, association with the receptor-interacting protein receptor activity-modifying protein-2 (RAMP2), and the role of individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.