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<p>Many GPCRs trigger a second phase of G protein-coupled signaling from endosomes after signaling from the plasma membrane, necessitating GPCRs to increase the concentration of active-state G proteins on the endosome membrane. How this is achieved remains unclear. Here, we show that three G<sub>s</sub>-coupled GPCRs–the β2-adrenergic receptor, VIP-1 receptor, and adenosine 2B receptor–each trigger a net redistribution of Gα<sub>s</sub> from the plasma membrane to endosomes at native expression levels and without requiring receptor internalization. We then show that active-state Gα<sub>s</sub> production on endosomes, in contrast, is GPCR internalization-dependent. We further identify location bias in the selectivity of GPCR coupling between G<sub>s</sub> and G<sub>q</sub> on endosomes relative to the plasma membrane. We propose that endosomal G<sub>s</sub> regulation involves discrete GPCR-G protein coupling reactions, one at the plasma membrane controlling G<sub>s</sub> concentration and another at endosomes controlling G<sub>s</sub> activity, and that GPCR endocytosis can switch signaling selectivity between G protein classes.</p>

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Conformational biosensors delineate endosomal G protein regulation by GPCRs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月18日

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  • Brian Wysolmerski,
  • Nicole M. Fisher,
  • Andrew N. Dates,
  • Asuka Inoue,
  • Emily E. Blythe,
  • Mark von Zastrow

摘要

Many GPCRs trigger a second phase of G protein-coupled signaling from endosomes after signaling from the plasma membrane, necessitating GPCRs to increase the concentration of active-state G proteins on the endosome membrane. How this is achieved remains unclear. Here, we show that three Gs-coupled GPCRs–the β2-adrenergic receptor, VIP-1 receptor, and adenosine 2B receptor–each trigger a net redistribution of Gαs from the plasma membrane to endosomes at native expression levels and without requiring receptor internalization. We then show that active-state Gαs production on endosomes, in contrast, is GPCR internalization-dependent. We further identify location bias in the selectivity of GPCR coupling between Gs and Gq on endosomes relative to the plasma membrane. We propose that endosomal Gs regulation involves discrete GPCR-G protein coupling reactions, one at the plasma membrane controlling Gs concentration and another at endosomes controlling Gs activity, and that GPCR endocytosis can switch signaling selectivity between G protein classes.