Functionally selective ligands to address specific cellular responses downstream of G protein-coupled receptors (GPCR) open up new possibilities for therapeutics. We designed and characterized novel subtype- and pathway-selective ligands. Substitution of position Q34 of neuropeptide Y to glycine (G34-NPY) results in unprecedented selectivity over all other YR subtypes. Moreover, this ligand displays a significant bias towards activation of the Gi/o pathway over recruitment of arrestin-3. Notably, no bias is observed for an established Y1R versus Y2R selective ligand carrying a proline at position 34 (F7,P34-NPY). Next, we investigated the spatio-temporal signaling at the Y1R and demonstrated that G protein-biased ligands promote a prolonged localization at the cell membrane, which leads to enhanced G protein signaling, while endosomal receptors do not contribute to cAMP signaling. Thus, spatial components are critical for the signaling of the Y1R that can be modulated by tailored ligands and represent a novel mode for biased pathways.

中文翻译：

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人类 Y1 受体的偏向激动剂会导致膜停留时间延长和受体 G 蛋白相互作用延长。


功能选择性配体可解决 G 蛋白偶联受体 (GPCR) 下游的特定细胞反应，为治疗开辟了新的可能性。我们设计并表征了新型亚型和途径选择性配体。将神经肽 Y 的 Q34 位替换为甘氨酸 (G34-NPY) 导致比所有其他 YR 亚型具有前所未有的选择性。此外，该配体对激活 Gi/o 途径表现出明显的偏向，而不是招募抑制蛋白-3。值得注意的是，对于已建立的在第 34 位携带脯氨酸的 Y1R 与 Y2R 选择性配体 (F7,P34-NPY) 没有观察到偏差。接下来，我们研究了 Y1R 的时空信号传导，并证明 G 蛋白偏向配体促进细胞膜上的长时间定位，从而导致 G 蛋白信号传导增强，而内体受体对 cAMP 信号传导没有贡献。因此，空间成分对于 Y1R 信号传导至关重要，Y1R 信号传导可以通过定制配体进行调节，并代表了偏向途径的一种新模式。