美国波士顿大学Mikel Garcia-Marcos研究组取得一项新突破。他们开发出直接探究生理背景依赖GPCR活性的通用生物传感器平台。这一研究成果于2024年2月26日发表在国际顶尖学术期刊《细胞》上。
课题组研究人员开发了一系列紧凑的ONE载体G蛋白光学(ONE-go)生物传感器，作为一个可扩展的平台，可以方便地应用到几乎任何GPCR上，即使在原代细胞中也能以高保真度测量G蛋白的激活。
通过对许多细胞类型（如原代心血管细胞或神经元）中的数十种GPCRs进行表征，研究人员揭示了GPCRs的G蛋白偶联选择性的分子基础、抗精神病药物对自然发生的GPCR变异体的药物基因组谱，以及内源性GPCRs根据细胞类型或诱导疾病样状态而产生的G蛋白亚型信号传导偏差。
总之，这个开放的平台使得直接探究生理背景依赖的的GPCR活性变得更加容易。
据介绍，G蛋白偶联受体（GPCRs）是人类基因组中编码的最大的可药物化蛋白家族，但由于缺乏在生理相关背景下可靠测量其细微行为的工具，对它们的理解和靶向性进展受到阻碍。
Title: Direct interrogation of context-dependent GPCR activity with a universal biosensor platform
Author: Remi Janicot, Marcin Maziarz, Jong-Chan Park, Jingyi Zhao, Alex Luebbers, Elena Green, Clementine Eva Philibert, Hao Zhang, Mathew D. Layne, Joseph C. Wu, Mikel Garcia-Marcos
Issue&Volume: 2024-02-26
Abstract: G protein-coupled receptors (GPCRs) are the largest family of druggable proteins encodedin the human genome, but progress in understanding and targeting them is hinderedby the lack of tools to reliably measure their nuanced behavior in physiologicallyrelevant contexts. Here, we developed a collection of compact ONE vector G-proteinOptical (ONE-GO) biosensor constructs as a scalable platform that can be convenientlydeployed to measure G-protein activation by virtually any GPCR with high fidelityeven when expressed endogenously in primary cells. By characterizing dozens of GPCRsacross many cell types like primary cardiovascular cells or neurons, we revealed insightsinto the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomicprofiles of anti-psychotics on naturally occurring GPCR variants, and G-protein subtypesignaling bias by endogenous GPCRs depending on cell type or upon inducing disease-likestates. In summary, this open-source platform makes the direct interrogation of context-dependentGPCR activity broadly accessible.
DOI: 10.1016/j.cell.2024.01.028
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00065-5