美国明尼苏达大学Sivaraj Sivaramakrishnan研究小组发现通过第三个胞内环对GPCR信号进行自我调节。该项研究成果于2023年3月8日在线发表在《自然》杂志上。

G蛋白偶联受体（GPCR）折叠的第三个胞内环（ICL3）对于受体激活下游的信号转导过程非常重要。尽管如此，由于缺乏明确的ICL3结构，加上其在GPCR之间的高度序列差异，使其参与受体信号传导的特征变得复杂化。以前对β₂肾上腺素受体（β₂AR）的研究表明，ICL3参与了受体激活和信号传导的结构过程。

研究人员对ICL3在β₂AR信号中的作用有了深入的了解，观察到ICL3通过阻断或暴露受体G蛋白结合位点的动态构象平衡，自动调节受体的活性。研究人员证明了这种平衡对受体药理学的重要性，表明G蛋白模拟效应物偏向于ICL3的暴露状态，从而异构激活受体。研究结果还显示，ICL3通过抑制受体与G蛋白亚型的耦合来调整信号的特异性，而G蛋白亚型与受体的耦合较弱。尽管ICL3的序列多种多样，但研究人员证明通过ICL3的这种负G蛋白选择机制延伸到整个超家族的GPCR，从而扩大了受体介导G蛋白亚型选择信号的已知机制范围。此外，这些研究结果表明，ICL3是受体和信号通路特异性配体的一个异构部位。

附：英文原文

Title: Autoregulation of GPCR signalling through the third intracellular loop

Author: Sadler, Fredrik, Ma, Ning, Ritt, Michael, Sharma, Yatharth, Vaidehi, Nagarajan, Sivaramakrishnan, Sivaraj

Issue&Volume: 2023-03-08

Abstract: The third intracellular loop (ICL3) of the G protein-coupled receptor (GPCR) fold is important for the signal transduction process downstream of receptor activation1,2,3. Despite this, the lack of a defined structure of ICL3, combined with its high sequence divergence among GPCRs, complicates characterization of its involvement in receptor signalling4. Previous studies focusing on the β2 adrenergic receptor (β2AR) suggest that ICL3 is involved in the structural process of receptor activation and signalling5,6,7. Here we derive mechanistic insights into the role of ICL3 in β2AR signalling, observing that ICL3 autoregulates receptor activity through a dynamic conformational equilibrium between states that block or expose the receptor’s G protein-binding site. We demonstrate the importance of this equilibrium for receptor pharmacology, showing that G protein-mimetic effectors bias the exposed states of ICL3 to allosterically activate the receptor. Our findings additionally reveal that ICL3 tunes signalling specificity by inhibiting receptor coupling to G protein subtypes that weakly couple to the receptor. Despite the sequence diversity of ICL3, we demonstrate that this negative G protein-selection mechanism through ICL3 extends to GPCRs across the superfamily, expanding the range of known mechanisms by which receptors mediate G protein subtype selective signalling. Furthermore, our collective findings suggest ICL3 as an allosteric site for receptor- and signalling pathway-specific ligands.

DOI: 10.1038/s41586-023-05789-z

Source: https://www.nature.com/articles/s41586-023-05789-z