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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=655082
• 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 GTPγS, 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) 受体是一种单通道多功能糖蛋白，包含一个大的胞外结构域和一个小的胞质尾部，该受体与 IGF-II 和 6-磷酸甘露糖 (M6P) 配体相互作用。 ，例如通过两个不同位点的溶酶体酶 大多数受体在反式高尔基体/内体区室中表达，并参与新合成的溶酶体的分离。位于质膜上的受体亚群调节含有 IGF-II 和 M6P 的配体的内化，以清除或激活受体二聚化在 M6P 的最佳结合和内化中发挥作用。目前，还有证据表明IGF-II受体通过激活特定的细胞内信号传导途径参与介导IGF-II的某些生物学作用。尽管该受体的运输作用已得到充分证实，但其在响应 IGF-II 结合的跨膜信号转导中的重要性仍然存在争议，我们使用多种方法报道了 i) 单程 IGF-II 受体与 G- 偶联。 Leu27IGF-II 蛋白及其被 Leu27IGF-II（一种优先与受体结合的 IGF-II 类似物）激活，增强乙酰胆碱释放，但减弱百日咳毒素从成年大鼠海马释放 GABA (PTX) 敏感途径和 ii) 受体的激活导致其从耐洗涤剂转位至可溶解洗涤剂的膜部分，并通过 PTX 依赖性途径刺激细胞外信号相关激酶 1/2。表明 i) GTP 类似物 GTPγS 抑制 [125I]IGF-II 而不是 M6P 配体 [125I]PMB-BSA 与 IGF-II 受体的结合，ii) PTX治疗减弱了海马培养神经元中 [125I]IGF-II 的内化，iii) Leu27IGF-II 增强海马谷氨酸释放并增强成人艺术中的空间学习因此，我们通过与 G 相互作用，开始使用单跨膜结构域 IGF-II 受体。 -蛋白质，可以直接调节成年大鼠大脑中IGF-II的生物学功能。为了解决这个问题，我们建议：i)确定IGF-II是否存在。受体介导的 G 蛋白信号传导可以在 M6P 配体存在的情况下发生，ii) 确定 IGF-II 受体的二聚化是否对其信号传导作用是必要的，iii) 确定诱导后 IGF-II 受体的命运iv) 确定谷氨酸和乙酰胆碱在 IGF-II 介导的认知功能增强中的作用IGF-II 受体和 G 蛋白，有助于确定其在调节正常大脑功能中的重要性。