Opioid receptors reveal a discrete cellular mechanism of endosomal G protein activation

• 成果类型: Article
• 署名作者: Fisher, Nicole M.; von Zastrow, Mark
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9209
• DOI: 10.1073/pnas.2420623122
• 发表日期: 2025-04-29
• 关键词: retromer; mu; TRAFFICKING; endocytosis; alpha; cells; camp

摘要

Many GPCRs initiate a second phase of G protein-mediated signaling from endosomes. This inherently requires the GPCR to increase cognate G protein activity on the endosome surface. Gs-coupled GPCRs are thought to achieve this by internalizing and mediating a second round of allosteric coupling to G proteins on the endosome membrane. Here, we provide evidence that the mu- opioid receptor (MOR), a Gi-coupled GPCR, is able to increase endosomal G protein activity in a different way. Leveraging conformational biosensors, we show that MOR activation triggers a transient increase of active-state Gi/o on the plasma membrane that is followed by a prolonged increase on endosomes. Contrary to the Gs-coupled GPCR paradigm, however, we show that the MOR-induced increase of active-state Gi/o on endosomes requires neither internalization of MOR nor the presence of activated MOR in the endosome membrane. We propose a distinct and additional cellular mechanism of endosomal signaling by Gi/o that is communicated through trafficking of the activated G protein rather than its activating GPCR.