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首页> 外文期刊>Cellular Physiology and Biochemistry >Dissecting the Conserved NPxxY Motif of the M3 Muscarinic Acetylcholine Receptor: Critical Role of Asp-7.49 for Receptor Signaling and Multiprotein Complex Formation
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Dissecting the Conserved NPxxY Motif of the M3 Muscarinic Acetylcholine Receptor: Critical Role of Asp-7.49 for Receptor Signaling and Multiprotein Complex Formation

机译：解剖M3毒蕈碱型乙酰胆碱受体的保守NPxxY基序：Asp-7.49受体信号和多蛋白复合物形成的关键作用。

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Acetylcholine challenge produces Msub3/sub muscarinic acetylcholine receptor activation and accessory/scaffold proteins recruitment into a signalsome complex. The dynamics of such a complex is not well understood but a conserved NPxxY motif located within transmembrane 7 and juxtamembrane helix 8 of the receptor was found to modulate G protein activation. Here by means of receptor mutagenesis we unravel the role of the conserved Msub3/sub muscarinic acetylcholine receptor NPxxY motif on ligand binding, signaling and multiprotein complex formation. Interestingly, while a N7.49D receptor mutant showed normal ligand binding properties a N7.49A mutant had reduced antagonist binding and increased affinity for carbachol. Also, besides this last mutant was able to physically couple to Gαsubq/11/sub after carbachol challenge it was neither capable to activate phospholipase C nor phospholipase D. On the other hand, we demonstrated that the Asn-7.49 is important for the interaction between Msub3/subR and ARF1 and also for the formation of the ARF/Rho/β γ signaling complex, a complex that might determine the rapid activation and desensitization of PLD. Overall, these results indicate that the NPxxY motif of the Msub3/sub muscarinic acetylcholine receptor acts as key conformational switch for receptor signaling and multiprotein complex formation.
机译：乙酰胆碱激发产生M 3 毒蕈碱型乙酰胆碱受体活化和辅助/支架蛋白募集进入信号复合体。这种复合物的动力学尚不清楚，但是发现位于受体的跨膜7和近膜螺旋8内的保守的NPxxY基序调节G蛋白的活化。在这里，通过受体诱变，我们揭示了保守的M 3 毒蕈碱型乙酰胆碱受体NPxxY基序对配体结合，信号传导和多蛋白复合物形成的作用。有趣的是，尽管N7.49D受体突变体显示出正常的配体结合特性，但N7.49A突变体却减少了拮抗剂的结合并增加了对咔巴酚的亲和力。此外，除了最后一个突变体在卡巴胆碱攻击后能够与Gα q / 11 物理偶联之外，它也无法激活磷脂酶C和磷脂酶D。另一方面，我们证明了Asn-7.49对于M 3 和ARF1之间的相互作用以及ARF / Rho /βγ信号复合物的形成非常重要，该复合物可能决定PLD的快速激活和脱敏。总体而言，这些结果表明，M 3 毒蕈碱型乙酰胆碱受体的NPxxY基序是受体信号传导和多蛋白复合物形成的关键构象转换。

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