GPR56/ADGRG1的G蛋白选择性概况及其对下游效应器的影响
Raida Jallouli1,2, Ana L Moreno-Salinas1,2, Andréanne Laniel1,2
1Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Cellular and molecular life sciences : CMLS
|September 4, 2024
概括
不同的GPR56配体通过不同的机制激活受体,影响G蛋白选择性. 这些通路汇聚在Rho通路激活上,这对于GPR56在生理和癌症环境中的功能至关重要.
科学领域:
- 细胞生物学 细胞生物学
- 分子药理学分子药理学
- G 蛋白结合受体的受体.
背景情况:
- GPR56是一种粘附性G蛋白结合受体 (aGPCR),表现出构成性和连接体促进活性.
- 它在生理和病理过程中的作用是显著的,但激活机制和功能选择性仍然不清楚.
研究的目的:
- 通过不同的配体来研究GPR56激活的分子机制.
- 为了确定不同的激活模式是否导致G蛋白 (G12和G13) 之间的功能选择性.
主要方法:
- 利用GPR56突变 (蛋白质分解缺陷和N-终端截断) 来研究激活机制.
- 评估了G蛋白激活 (G12,G13) 和β-arrestin的使用情况.
- 研究了BT-20乳腺癌细胞中的Rho通路激活.
主要成果:
- 构成性地激活了G12和G13的GPR56.
- 抗体10C7倾向于G13激活而不是G12,独立于绑定的激动剂.
- 3-α-acetoxydihydrodeoxygedunin (3αDOG) 的激活需要蛋白质分解,而不是10C7.7.
- 这两种连接体都汇聚在癌细胞中的Rho通路激活上.
结论:
- 不同的GPR56配体采用不同的激活模式,导致不同的G蛋白选择性.
- 这些多样化的激活通路汇聚在Rho通路上,突出显示了它在GPR56信号传输中的重要性.
- 抗体10C7是研究GPR56活性及其在癌症中的作用的宝贵工具.
相关概念视频
Activation and Inactivation of G Proteins
6.9K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.9K
GPCRs Regulate Adenylyl Cylase Activity
5.4K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.4K
Transducer Mechanism: G Protein–Coupled Receptors
1.9K
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
GPCRs are also called heptahelical,...
1.9K
G Protein-coupled Receptors
11.6K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
11.6K
G-protein Coupled Receptors
117.1K
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
117.1K
GPCR Desensitization
5.9K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
5.9K


