In a new study at University of California, Irvine, researchers have revealed the impact of native lipids on rhodopsin signaling and regeneration, which may usher in a new paradigm for discovery of drugs that target G protein-coupled receptors (GPCRs).

GPCR是细胞表面受体，对各种刺激有反应，以激活跨细胞膜的信号通路。所有GPCR都是膜结合的，很少在其本机膜环境中进行研究。最近的进展产生了脂质在介导信号传导中的关键中间体和作用的原子结构。然而，直到现在，捕获野生型受体的信号事件，横跨其下游效应器的本地膜，一直难以捉摸。到目前为止，这些受体代表了最大的药物靶标，并且大量认可的药物调节其功能。

In this new study published today in自然, titled, “Capturing a rhodopsin receptor signaling cascade across a native membrane,” the researchers, using mass spectrometry, probed the archetype class A GPCR, rhodopsin, directly in fragments of native disc membranes. They monitored real-time photoconversion of dark-adapted rhodopsin to opsin, delineating the stepwise isomerization of retinal and hydrolysis of the retinal-opsin adduct, further discovering that the reaction is significantly slower in its natural membrane environment than in artificial detergent micelles.

“Human diseases, ranging from cancer to cardiovascular diseases to blindness, are all highly impacted by the function of GPCRs. In addition to quantitative analysis of the signaling function, this novel technology, for the first time, has enabled direct detection of new potential targets of therapeutic value for the visual system, within the native membranes. I am convinced that analogous work will be done on many other GPCR systems, ” explainedKrzysztof Palczewski，博士UCI医学院和共同对应作家的唐纳德·布伦眼科教授。

Considering the lipids ejected with rhodopsin from the membrane fragments in the mass spectrometer, researchers were able to demonstrate that opsin can be regenerated in the membranes through photoisomerized retinal-lipid conjugates, and to obtain evidence for increased association of rhodopsin with unsaturated long-chain phosphatidylcholine during signal transduction.

该团队还捕获了视紫红质激活后信号级联的次要步骤。监测透明蛋白（GT）的光激活和鸟苷二磷酸（GDP）的解离以产生中间体apotrimeric G protein, they observed Gta。GTP subunits interacting with phosphodiesterase 6 (PDE6), found in cone and rod photoreceptor cells, which hydrolyzes the second messenger molecule cyclic guanosine monophosphate (cGMP).

“通过施加靶向视紫红质的化合物，我们已经显示了它们如何刺激或抑制信号传导via帕尔克斯基说：Rhodopsin-oppin和跨丁蛋白信号通路。”“使用瞬时的光闪光，与质谱仪上的记录同步，我们能够捕获信号传导级联，并在若云光蛋白信号传导中演示脂质和配体的作用。这项工作凸显了在本地环境中发现药物发现的新机会，并可能导致一种研究膜结合受体药理学的新比利时罗马尼亚比分直播方法。”

参考：Chen S，Getter T，Salom D等。捕获跨天然膜的视紫红质受体信号传导级联反应。自然。2022：1-7。doi：10.1038/s41586-022-04547-x

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