SIGNIFICANCE OF THE MULTIFUNCTIONAL INSULIN-LIKE GROWTH FACTOR-II RECEPTOR IN REGULATING NORMAL BRAIN FUNCTION

多功能胰岛素样生长因子 II 受体在调节正常脑功能中的意义

• 批准号: RGPIN-2017-05729
• 负责人: Kar, Satyabrata
• 金额: $ 1.89万
• 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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=681670
• 关键词: SIGNIFICANCE; MULTIFUNCTIONAL; INSULIN; LIKE; GROWTH

The insulin-like growth factor-II (IGF-II) receptor is a single-pass multifunctional glycoprotein containing a large extracellular domain and a small cytoplasmic tail. The receptor interacts with IGF-II and mannose 6-phosphate (M6P)-bearing ligands, such as lysosomal enzymes via two distinct sites. Majority of the receptors are expressed within trans-Golgi/endosomal compartments and are involved in the segregation of newly synthesized lysosomal enzymes for sorting to endosomes/lysosomes. A subset of receptors located on the plasma membrane regulates internalization of IGF-II and M6P-containing ligands for their clearance or activation. Receptor dimerization has been suggested to play a role in optimal binding and internalization of M6P-bearing ligands. There is also evidence that the IGF-II receptor participates in mediating certain biological actions of IGF-II by activating specific intracellular signaling pathways. At present, while the trafficking role of the receptor is well established, its significance in transmembrane signaling in response to IGF-II binding remains controversial. Using a variety of approaches, we have reported that i) the single-pass IGF-II receptor is coupled to a G-protein and its activation by Leu27IGF-II, an IGF-II analog that binds preferentially to the receptor, potentiates acetylcholine release but attenuates GABA release from adult rat hippocampus by a pertussis toxin (PTX)-sensitive pathway and ii) activation of the receptor leads to its translocation from detergent-resistant to detergent-soluble membrane fractions and stimulation of extracellular signal-related kinase 1/2 via a PTX-dependent pathway. Our recent preliminary data further indicate that i) binding of [125I]IGF-II but not the M6P ligand [125I]PMB-BSA to the IGF-II receptor is inhibited by GTP analogue GTPS, ii) PTX treatment attenuates internalization of [125I]IGF-II in hippocampal cultured neurons, iii) Leu27IGF-II potentiates hippocampal glutamate release and enhances spatial learning in adult arts. Thus, we hypothesize that single transmembrane domain IGF-II receptor, by interaction with a G-protein, can directly regulate biological functions of IGF-II in the adult rat brain. To address this issue we propose: i) to determine whether IGF-II receptor-mediated G-protein signaling can occur in the presence of M6P-ligands, ii) to establish if dimerization of the IGF-II receptor is necessary for its signaling effects, iii) to determine the fate of the IGF-II receptor following induction of G-protein-mediated signaling cascade and iv) to establish the role of glutamate and acetylcholine in IGF-II-mediated enhancement of cognitive function. We believe that this study should generate original data regarding specificity of interactions between the IGF-II receptor and G protein and help to define its significance in regulating normal brain functions.

胰岛素样生长因子-II（IGF-II）受体是一种单次多功能糖蛋白，含有大细胞外域和小细胞质尾巴。该受体与IGF-II和6-磷酸甘露糖（M6P）的含量配体相互作用，例如通过两个不同的位点，例如溶酶体酶。大多数受体在反式高尔基/内体室内表达，并参与新合成的溶酶体酶的分离，以分类内体/溶酶体。位于质膜上的受体的子集调节IGF-II和含M6P的配体的内在化，以清除或激活。已经建议受体二聚化在含M6P配体的最佳结合和内在化中发挥作用。也有证据表明，IGF-II受体通过激活特定的细胞内信号通路来介导IGF-II的某些生物学作用。目前，虽然受体的运输作用已经很好地确定，但其在跨膜信号中的重要性仍然存在争议。 Using a variety of approaches, we have reported that i) the single-pass IGF-II receptor is coupled to a G-protein and its activation by Leu27IGF-II, an IGF-II analog that binds preferentially to the receptor, potentiates acetylcholine release but attenuates GABA release from adult rat hippocampus by a pertussis toxin (PTX)-sensitive途径和II）受体的激活导致其从耐洗涤剂到洗涤剂可溶性膜的易位，并通过依赖PTX依赖性途径刺激细胞外信号相关激酶1/2。 Our recent preliminary data further indicate that i) binding of [125I]IGF-II but not the M6P ligand [125I]PMB-BSA to the IGF-II receptor is inhibited by GTP analogue GTPS, ii) PTX treatment attenuates internalization of [125I]IGF-II in hippocampal cultured neurons, iii) Leu27IGF-II增强海马谷氨酸并增强成人艺术中的空间学习。因此，我们假设通过与G蛋白相互作用，单个跨膜结构域IGF-II受体可以直接调节成年大鼠脑中IGF-II的生物学功能。 To address this issue we propose: i) to determine whether IGF-II receptor-mediated G-protein signaling can occur in the presence of M6P-ligands, ii) to establish if dimerization of the IGF-II receptor is necessary for its signaling effects, iii) to determine the fate of the IGF-II receptor following induction of G-protein-mediated signaling cascade and iv) to establish the role of glutamate and IGF-II介导的认知功能增强中的乙酰胆碱。我们认为，这项研究应生成有关IGF-II受体和G蛋白之间相互作用特异性的原始数据，并有助于定义其在调节正常脑功能方面的重要性。