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

胰岛素样生长因子-II(IGF-II)受体是一种单一的跨膜糖蛋白，含有一个大的胞外结构域和一个小的胞浆尾巴。该受体通过两个不同的位点与IGF-II和含甘露糖6-磷酸的溶酶体酶相互作用。大多数受体表达在跨高尔基体网络/内体隔室，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。位于质膜上的一组受体调节分泌的溶酶体酶的内吞作用，介导IGF-II的内化和降解。与细胞内转运不同，IGF-II受体在IGF-II跨膜信号传递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，其被IGF-II或Leu27IGF-II激活，IGF-II或Leu27IGF-II是一种优先与IGF-II受体结合的类似物，通过G蛋白敏感的途径增强乙酰胆碱的释放，但减少大鼠海马区GABA的释放。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β-arrestin-2相关，并在激动剂刺激下从洗涤剂抗性膜组分转移到洗涤剂可溶性膜组分。这些结果使我们推测，大脑中的单个跨膜区IGF-II受体与G蛋白偶联，其激活可以通过触发G蛋白连接的细胞内信号机制来介导特定的生物反应。为了解决这个问题，我们建议：1)建立IGF-II受体与G蛋白/β-arrestin-2相互作用的特异性；ii)评价IGF-II受体是否与G蛋白直接或间接相互作用；iii)确定IGF-II抑制海马区GABA释放的机制；iv)研究IGF-II受体过表达转基因小鼠脑内GABA能和胆碱能系统的变化。我们相信，这项研究不仅应该为IGF-II受体在正常脑中的生理意义提供证据，而且也将为更好地理解它在神经退行性疾病中的作用铺平道路。

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.