Single transmembrane domain insulin-like growth factor-II receptor and G protein: potential interaction and its significance in brain function

单跨膜结构域胰岛素样生长因子-II 受体和 G 蛋白：潜在的相互作用及其对脑功能的意义

• 批准号: 203518-2011
• 负责人: Kar, Satyabrata
• 金额: $ 2.91万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=593827
• 关键词: Single; transmembrane; domain; insulin; like

The insulin-like growth factor-II (IGF-II) receptor is a single transmembrane glycoprotein containing a large extracellular domain and small cytoplasmic tail. The receptor interacts with the IGF-II and mannose 6-phosphate-bearing lysosomal enzymes via two distinct sites. A majority of the receptors are expressed within trans-Golgi network/endosomal compartments, where they divert newly synthesized lysosomal enzymes from the secretory pathway to endosomes and lysosomes. A subset of receptors located on the plasma membrane regulates endocytosis of secreted lysosomal enzymes, mediates internalization and degradation of IGF-II. Unlike intracellular trafficking, the role of the IGF-II receptor in the transmembrane signaling of IGF-II remains poorly understood. We have recently reported that the IGF-II receptor of the brain is coupled to a G protein and its activation by IGF-II or Leu27IGF-II, an analog that binds preferentially to the IGF-II receptor, potentiates acetylcholine release but decrease GABA release from the rat hippocampus by a G protein-sensitive pathway. Additionally, we observed that IGF-II receptors are associated with G protein-coupled receptor interacting protein beta-arrestin-2 and are translocated from detergent-resistant membrane to detergent-soluble membrane fractions following stimulation with agonist. These results led us to hypothesize that the single transmembrane domain IGF-II receptor in the brain is coupled to a G-protein and its activation can mediate specific biological responses by triggering G protein-linked intracellular signaling mechanism. To address this issue we propose i) to establish the specificity of the IGF-II receptor interaction with G protein/beta-arrestin-2, ii) to evaluate whether the IGF-II receptor interacts directly or indirectly with the G protein, iii) to determine the mechanisms by which IGF-II attenuates hippocampal GABA release and iv) to study alterations in the GABAergic and cholinergic systems in the brain of IGF-II receptor overexpressing transgenic mice. We believe that this study should not only provide evidence for the physiological relevance of IGF-II receptor in normal brain but it will also pave the way for a better understanding of its role in neurodegenerative diseases.

胰岛素样生长因子-II (IGF-II) 受体是一种单跨膜糖蛋白，含有大的胞外结构域和小的胞质尾。该受体通过两个不同的位点与 IGF-II 和甘露糖 6-磷酸溶酶体酶相互作用。大多数受体在跨高尔基体网络/内体区室中表达，在那里它们将新合成的溶酶体酶从分泌途径转移到内体和溶酶体。位于质膜上的受体子集调节分泌的溶酶体酶的内吞作用，介导 IGF-II 的内化和降解。与细胞内运输不同，IGF-II 受体在 IGF-II 跨膜信号传导中的作用仍然知之甚少。我们最近报道，大脑的 IGF-II 受体与 G 蛋白偶联，并被 IGF-II 或 Leu27IGF-II（一种优先与 IGF-II 受体结合的类似物）激活，增强乙酰胆碱的释放，但减少 GABA 的释放通过 G 蛋白敏感途径从大鼠海马体中提取。此外，我们观察到 IGF-II 受体与 G 蛋白偶联受体相互作用蛋白 beta-arrestin-2 相关，并在激动剂刺激后从耐去污剂膜易位至去污剂可溶性膜部分。这些结果使我们推测大脑中的单跨膜结构域IGF-II受体与G蛋白偶联，其激活可以通过触发G蛋白相关的细胞内信号传导机制来介导特定的生物反应。为了解决这个问题，我们建议 i) 确定 IGF-II 受体与 G 蛋白/β-arrestin-2 相互作用的特异性，ii) 评估 IGF-II 受体是否直接或间接与 G 蛋白相互作用，iii)确定 IGF-II 减弱海马 GABA 释放的机制，以及 iv) 研究 IGF-II 受体过表达转基因小鼠大脑中 GABA 能和胆碱能系统的变化。我们相信，这项研究不仅应该为正常大脑中 IGF-II 受体的生理相关性提供证据，而且还将为更好地了解其在神经退行性疾病中的作用铺平道路。