Mechanisms and function of spatially encoded GPCR signaling

空间编码GPCR信号转导的机制和功能 项目概述：G蛋白偶联受体（GPCRs），一类重要的信号传导器， 在人体中普遍表达，并且几乎可以检测所有类型的刺激。因此，这些 跨膜受体控制着人体所有基本的生理机能，几乎占到了电流的一半。 治疗目标所有已知的作用于GPCR的药物都是基于以下假设开发的： 在细胞表面启动的信号是需要调节的主要过程。然而，在这方面， 我们和其他人最近的工作颠覆了GPCR信号转导的“经典”模型， 这表明受体在细胞内是活跃的。此外，我们已确定， 活性GPCR的定位可以指定功能上不同的细胞反应，并可以塑造如何 细胞通过相同的受体解释不同的药物。利用这些见解 研究结果，我们的目标是提供一个全面的解剖细胞功能和分子 区室化GPCR信号传导的基础。具体而言，在本提案中，我们将剖析如何 空间编码的反应是建立在多个层次上，从分子决定因素内， GPCR本身、下游效应物和细胞类型特异性机制。此外，我们将执行 对已知受体区室引发的下游反应的综合分析 活动，以确定局部信号的后果。这一建议是基于我们的 在高通量定量方法、成像、药理学和细胞生物学方面具有优势。这些 研究将阐明细胞信号转导的基本原理，并使我们能够重新认识 探索GPCR药理学的分子决定因素，以有效地靶向这些 疾病的路径。

Mechanisms and function of spatially encoded GPCR signaling PROJECT SUMMARY: G protein-coupled receptors (GPCRs), a critical class of signal transducers, are ubiquitously expressed in the human body and can detect virtually all types of stimuli. As such, these transmembrane receptors control all essential human physiology, and account for almost half of current therapeutic targets. All of the known drugs acting on GPCRs were developed on the assumption that signals initiated at the cell surface were the primary process that needed to be regulated. However, recent work by us and others has upended this `classical' model of GPCR signal transduction by demonstrating that receptors can be active inside the cell. Furthermore, we have established that localization of the active GPCR can specify functionally distinct cellular responses and could shape how cells interpret different drugs acting through the same receptor. Leveraging the insights from these findings, we aim to provide a comprehensive dissection of the cellular functions and molecular underpinnings of compartmentalized GPCR signaling. Specifically, in this proposal we will dissect how spatially encoded responses are established across multiple levels, from molecular determinants within the GPCR itself, to downstream effectors, and cell-type specific mechanisms. Further, we will carry out comprehensive analysis of the downstream responses triggered by known compartments of receptor activity to determine the consequences of localized signaling. This proposal is anchored in our strengths in high-throughput quantitative methods, imaging, pharmacology, and cell biology. These studies will elucidate fundamental principles governing cellular signal transduction, and allow us to re- explore the molecular determinants of GPCR pharmacology in order to effectively target these pathways in disease.