Programming GPCR signalling within the endocytic network; mechanisms and therapeutic applications

在内吞网络内编程 GPCR 信号传导；

• 批准号: BB/S001565/1
• 负责人: Aylin Hanyaloglu
• 金额: $ 73.21万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS001565%2F1
• 关键词: Programming; GPCR; signalling; within; endocytic

Cells communicate to each other by sending and responding to chemical messages. Coordinating this communication is essential for correct functioning of every organ in the body. These messages include photons of light, chemicals that we smell, the food that we eat, mineral ions such as calcium, hormones and neurotransmitters (chemical messengers of the brain). The chemical messages are received when they bind to specific proteins on the cell surface called receptors, which relay the message in to the cell. Our research is focussed on a family of receptors called G protein-coupled receptors (GPCRs). Our genes encode for more than 800 different kinds of GPCRs that are capable of responding to numerous different messages. Each organ in the body has many different GPCRs. Importantly, the function of these receptors is disrupted in various diseases and disorders, including cancer, obesity, diabetes, blindness, heart disease, depression, Parkinson's Disease, recurrent miscarriage and pre-term birth, to name but a few. Although many prescribed drugs target GPCRs, there is a high demand for new compounds that are more specific, have fewer side effects, and that are active for longer. Developing these new drugs requires an in-depth understanding of the molecular machinery that controls the activity these receptors.Once any cell receives external messages that bind to GPCRs, the activated receptors will relay specific signals to elicit an appropriate cellular response. This process is tightly controlled by the cell. One important mechanism is the rapid removal, or trafficking, of receptors from the cell surface in to interior compartments called endosomes, as a means of switching off these signals. However, we discovered that certain GPCRs recruited to specialized endosomes, which we termed very early endosomes (VEE), can switch on new signalling pathways. So, both duration and location of signals generated by GPCRs creates patterns that are critical for the cell, telling it whether to release more chemicals, activate particular genes, divide, or even die. If such signalling patterns are disrupted, or misdirected, they can lead to disease. However, our discovery also raises the possibility that drugs can be developed to redirect the receptor and change its function in a cell. The aim of this project is to understand how a cell controls receptor activity by examining the molecules involved in trafficking and signal decoding of GPCRs from the VEE. Our recent work also revealed that trafficking to the VEE of a GPCR important in reproduction and in early pregnancy (the LH receptor) may be important in how the uterus responds to hormones produced by the embryo in early pregnancy, and that these pathways may be altered in women suffering recurrent miscarriage. We will also assess the role of this compartment to other GPCRs by studying a receptor important in sensing carbohydrates in our food (the FFA2 receptor) and another that is targeted in IVF, cancer and menopause (the FSH receptor). For FSH and LH receptor we will determine whether drugs can alter the trafficking of specific GPCRs to the VEE or other endosomal compartments, and in turn impact on receptor activity. The outcome of this work will help us understand fundamental mechanisms of how cells communicate. As GPCRs are common drug targets, detailed knowledge of how GPCRs are regulated by the VEE may even provide new avenues for more effective treatments of a number of conditions that involve this superfamily of receptors.

细胞通过发送和响应化学信息来相互交流。协调这种沟通对于体内每个器官的正确运作至关重要。这些信息包括光的光子、我们闻到的化学物质、我们吃的食物、钙等矿物离子、激素和神经递质（大脑的化学信使）。当化学信息与细胞表面称为受体的特定蛋白质结合时，化学信息就会被接收，受体将信息传递给细胞。我们的研究重点是称为 G 蛋白偶联受体 (GPCR) 的受体家族。我们的基因编码 800 多种不同类型的 GPCR，这些 GPCR 能够响应多种不同的信息。身体的每个器官都有许多不同的 GPCR。重要的是，这些受体的功能在各种疾病和病症中受到破坏，包括癌症、肥胖、糖尿病、失明、心脏病、抑郁症、帕金森病、反复流产和早产等。尽管许多处方药物都以 GPCR 为靶标，但人们对特异性更强、副作用更少且活性时间更长的新化合物的需求很高。开发这些新药需要深入了解控制这些受体活性的分子机制。一旦任何细胞接收到与 GPCR 结合的外部信息，激活的受体就会传递特定信号以引发适当的细胞反应。这个过程受到细胞的严格控制。一个重要的机制是受体从细胞表面快速去除或运输到称为内体的内部区室，作为关闭这些信号的一种手段。然而，我们发现某些GPCR被招募到专门的内体中，我们将其称为极早期内体（VEE），可以开启新的信号通路。因此，GPCR 产生的信号的持续时间和位置都会产生对细胞至关重要的模式，告诉细胞是否释放更多化学物质、激活特定基因、分裂甚至死亡。如果这些信号传导模式被破坏或误导，就会导致疾病。然而，我们的发现也提出了开发药物来改变受体并改变其在细胞中功能的可能性。该项目的目的是通过检查参与 VEE 中 GPCR 运输和信号解码的分子来了解细胞如何控制受体活性。我们最近的工作还表明，在生殖和妊娠早期（LH 受体）中重要的 GPCR（LH 受体）转运至 VEE 可能对于子宫如何响应妊娠早期胚胎产生的激素很重要，并且这些途径可能会发生改变患有反复流产的女性。我们还将通过研究对感知食物中的碳水化合物很重要的受体（FFA2 受体）和另一个针对 IVF、癌症和更年期的受体（FSH 受体）来评估该区室对其他 GPCR 的作用。对于 FSH 和 LH 受体，我们将确定药物是否可以改变特定 GPCR 向 VEE 或其他内体区室的运输，进而影响受体活性。这项工作的成果将帮助我们了解细胞如何沟通的基本机制。由于 GPCR 是常见的药物靶点，因此详细了解 VEE 如何调节 GPCR 甚至可能为更有效地治疗涉及该受体超家族的多种疾病提供新途径。

项目成果

Pharmacological Characterization of Low Molecular Weight Biased Agonists at the Follicle Stimulating Hormone Receptor.

低分子量偏向卵泡激素受体激动剂的药理学特征。

• DOI: http://dx.10.3390/ijms22189850
• 发表时间: 2021
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: De Pascali F

Genetically encoded intrabody sensors report the interaction and trafficking of ß-arrestin 1 upon activation of G-protein-coupled receptors.

基因编码的体内传感器报告 G 蛋白偶联受体激活后 α-arrestin 1 的相互作用和运输。

• DOI: http://dx.10.1074/jbc.ra120.013470
• 发表时间: 2020
• 期刊: The Journal of biological chemistry
• 作者: Baidya M

Distinct phosphorylation sites in a prototypical GPCR differently orchestrate ß-arrestin interaction, trafficking, and signaling.

原型 GPCR 中不同的磷酸化位点以不同方式协调 α-arrestin 相互作用、运输和信号传导。

• DOI: http://dx.10.1126/sciadv.abb8368
• 发表时间: 2020
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Dwivedi

Reduced FSH and LH action: implications for medically assisted reproduction.

FSH 和 LH 作用降低：对医学辅助生殖的影响。

• DOI: http://dx.10.1093/humrep/deab065
• 发表时间: 2021
• 期刊: Human reproduction (Oxford, England)
• 作者: Bosch E

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders.

Kisspeptin 受体激动剂具有治疗女性生殖疾病的潜力。

• DOI: http://dx.10.1172/jci139681
• 发表时间: 2020
• 期刊: The Journal of clinical investigation
• 作者: Abbara A