G protein-coupled receptors (GPCRs) are the largest family of druggable proteins encoded in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically relevant contexts. Here, we developed a collection of compact ONE vector G-protein Optical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states. In summary, this open-source platform makes the direct interrogation of context-dependent GPCR activity broadly accessible.

中文翻译：

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使用通用生物传感器平台直接询问上下文相关的 GPCR 活性

G 蛋白偶联受体 (GPCR) 是人类基因组中编码的最大的可药物蛋白家族，但由于缺乏可靠测量其在生理相关环境中细微行为的工具，阻碍了对它们的理解和靶向进展。在这里，我们开发了一系列紧凑型 ONE 载体 G 蛋白光学 (ONE-GO) 生物传感器构建体，作为一个可扩展的平台，可以方便地部署，以测量几乎任何 GPCR 的高保真度 G 蛋白激活，即使在原代细胞中内源表达时也是如此。通过表征多种细胞类型（如原代心血管细胞或神经元）中的数十个 GPCR，我们揭示了对 GPCR G 蛋白偶联选择性的分子基础、抗精神病药物对天然 GPCR 变体的药物基因组学特征以及 G 蛋白亚型信号转导的见解内源性 GPCR 的偏差取决于细胞类型或诱导疾病样状态。总之，这个开源平台可以广泛地直接询问上下文相关的 GPCR 活动。