Nat：捕捉跨天然膜的视紫红质受体信号级联 膜电位变化光感

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Nature:捕捉跨天然膜的视紫红质受体信号级联  膜电位变化产生光感

领研网

2022/04/24

论文
论文标题：Capturing a rhodopsin receptor signalling cascade across a native membrane
作者：Siyun Chen, Tamar Getter, David Salom, Di Wu, Daniel Quetschlich, Dror S. Chorev, Krzysztof Palczewski & Carol V. Robinson
期刊：Nature
发表时间：2022/04/06
数字识别码：10.1038/s41586-022-04547-x
摘要：G protein-coupled receptors (GPCRs) are cell-surface receptors that respond to various stimuli to induce signalling pathways across cell membranes. Recent progress has yielded atomic structures of key intermediates1,2 and roles for lipids in signalling3,4. However, capturing signalling events of a wild-type receptor in real time, across a native membrane to its downstream effectors, has remained elusive. Here we probe the archetypal class A GPCR, rhodopsin, directly from fragments of native disc membranes using mass spectrometry. We monitor real-time photoconversion of dark-adapted rhodopsin to opsin, delineating retinal isomerization and hydrolysis steps, and further showing that the reaction is significantly slower in its native membrane than in detergent micelles. Considering the lipids ejected with rhodopsin, we demonstrate that opsin can be regenerated in membranes through photoisomerized retinal–lipid conjugates, and we provide evidence for increased association of rhodopsin with unsaturated long-chain phosphatidylcholine during signalling. Capturing the secondary steps of the signalling cascade, we monitor light activation of transducin (Gt) through loss of GDP to generate an intermediate apo-trimeric G protein, and observe Gαt•GTP subunits interacting with PDE6 to hydrolyse cyclic GMP. We also show how rhodopsin-targeting compounds either stimulate or dampen signalling through rhodopsin–opsin and transducin signalling pathways. Our results not only reveal the effect of native lipids on rhodopsin signalling and regeneration but also enable us to propose a paradigm for GPCR drug discovery in native membrane environments.

所属学科：
结构生物学

（导读 阿金）G蛋白偶联受体（GPCRs）是细胞表面受体，响应各种刺激诱导跨越细胞膜的信号传导通路。本研究使用质谱法在天然圆盘膜片段上直接探测典型的A类GPCR：视紫红质，实时监测了适应黑暗的视紫红质向视蛋白的转变过程，描述了视网膜的异构化过程以及水解步骤，并表明该反应在天然膜中的速度要明显慢于去污剂胶粒中。而且视紫红质可以通过光异构化视网膜-脂质共轭物在膜中再生。结果揭示了天然脂质在视紫红质信号传导和再生过程中的作用，为天然膜环境中的GPCR药物研发提供新范式。

文章标签
G蛋白偶联受体
视紫红质
视蛋白
异构化过程
水解

https://www.nature.com/articles/s41586-022-04547-x

https://www.linkresearcher.com/t ... d-96cf-2d01f598a5a7



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