Subcellular organization of Adhesion G-Protein Coupled Receptor (aGPCR) signalling.

粘附 G 蛋白偶联受体 (aGPCR) 信号传导的亚细胞组织。

• 批准号: RGPIN-2019-06166
• 负责人: Ramachandran, Rithwik
• 金额: $ 2.33万
• 依托单位: University of Western Ontario
• 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=684444
• 关键词: Subcellular; organization; Adhesion; Protein; Coupled

The long-term objectives of my research program are to understand G-protein coupled receptor function. G-protein-coupled receptors (GPCRs) sense and traduce signals from numerous effector molecules and play an essential role in coordinating the ability of cells to rapidly respond to its environment. Specifically, my research is focused on understanding function of non-canonically activated G-protein coupled receptors (GPCRs). This proposal will focus on the Adhesion G-protein-coupled Receptor-G1 (ADGRG1; also known as GPR56). ADGRG1 is a member of the autocatalytically activated Adhesion Family of GPCRs.******ADGRG1 undergoes an auto-catalytic event at a site called the GPCR proteolysis site (GPS), that results in the cell surface expression of a heterodimer consisting of 2 chains, a large extracellular N-terminal fragment (ADGRG1-NT) and a membrane-bound C-terminal fragment (ADGRG1-CT) which remain associated and non-covalently linked. It is believed that the ADGRG-NT is removed from ADGRG-CT through binding to extracellular matrix components and shear force resulting in ADGRG1-CT disinhibition, release and engagement of a tethered ligand and receptor signalling through G--proteins and --arrestin.******The unique proteolytic mode of activation for ADGRG1 results in irreversible activation and these receptors are often described as “one and done” GPCRs. This is in contrast to the reversible binding of a soluble hormone that activates most well studies GPCRs such as the 2--adrenergic receptor (2-AR) or the angiotensin II receptor type 1 (AT1) that are frequently recycled back to the cell surface following internalization and dissociation of the ligand from the receptor. It follows that adhesion GPCRs might engage intracellular sorting mechanisms and compartmentalized signalling that are distinct from those for soluble hormone binding GPCRs.******Overarching hypothesis: ADGRG1 engages intracellular vesicular trafficking and signalling pathways that are distinct from other hormone activated GPCRs such as 2-AR and AT1 as a result of irreversible auto-catalytic activation.******In order to understand ADGRG1 signalling and trafficking, in the short-term, we will:******Aim 1. Define ADGRG1 C-terminal tail amino acid sequences regulating interaction with the --arrestins.***Aim 2. Define the vesicular trafficking route for internalization of ADGRG1 and the vesicular trafficking route for de-novo synthesized receptor trafficking to the cell membrane.***Aim 3. Define the cell surface and endosomal signalling repertoire for ADGRG1. ******Significance: These studies will address fundamental questions regarding the signaling and vesicular transport mechanisms of a non-canonically activated GPCR. Given the important physiological roles and unique mechanisms of activation of this class of receptors, it is likely that these studies will reveal the diversity of pathways and mechanisms regulating the signaling and endocytic fate of GPCRs.

我的长期目标是从众多的效力和发挥作用，并在协调细胞迅速响应的能力中的重要作用建议将重点放在G蛋白偶联受体G1（ADGRG1；也称为GPR56）上。由2条链组成的异二聚体的细胞表面表达，一个大的细胞外N末端片段（ADGRG1-NT）和一个膜结合的C末端片段（ADGRG1-CT）共链接。通过与额外基质组件结合的ADGRG-CT和某些力通过G蛋白和-Arrestin产生ADGRG1-CT抑制配体和受体信号，而******则是独特的蛋白水解激活模式。被描述为“一项和完成”的GPCR。从受体中进行的igand。作为2-AR和AT1的自动催化性。 **AIM 2。对细胞膜的运输。 Tivived GPCR将揭示调节GPCR信号传导和内吞命运的途径的多样性。