G protein-coupled receptors (GPCRs) mediate the effects of numerous hormones and neurotransmitters and are major pharmacological targets. Classical studies with crude cell lysates or membrane preparations have identified the main biochemical steps involved in GPCR signaling. Moreover, recent studies on purified proteins have provided astounding details at the atomic level of the 3-D structures of receptors in multiple conformations, including in complex with G proteins and β-arrestins. However, several fundamental questions remain regarding the highly specific effects and rapid nature of GPCR signaling. Recent developments in single-molecule microscopy are providing important contributions to answering these questions. Overall, single-molecule studies have revealed unexpected levels of complexity, with receptors existing in different conformations and dynamically interacting among themselves, their signaling partners, and structural elements of the plasma membrane to produce highly localized signals in space and time. These findings may provide a new basis to develop innovative strategies to modulate GPCR function for pharmacological purposes.

中文翻译：

---

单分子水平的G蛋白偶联受体药理学。

G蛋白偶联受体（GPCR）介导多种激素和神经递质的作用，是主要的药理靶标。关于粗细胞裂解物或膜制备物的经典研究已经确定了GPCR信号转导涉及的主要生化步骤。此外，最近对纯化蛋白的研究提供了多种构型的受体3-D结构原子级的惊人细节，包括与G蛋白和β-arrestin的复合体。但是，关于GPCR信号的高度特异性作用和快速性质，仍然存在一些基本问题。单分子显微镜的最新发展为回答这些问题提供了重要的贡献。总体而言，单分子研究显示出出乎意料的复杂程度，受体以不同的构型存在，并在它们自身，其信号伴侣和质膜的结构元素之间动态相互作用，从而在空间和时间上产生高度局部的信号。这些发现可能为开发创新策略以调节GPCR功能以达到药理学目的提供新的依据。