G-protein regulatory network governs receptor internalization dynamics

• 成果类型: Article
• 署名作者: Rowe, Jacob B.; Pandey, Shubhi; Mayer, Ryan A.; Ludlam, W. Grant; Drube, Julia; Inoue, Asuka; Hoffmann, Carsten; Martemyanov, Kirill A.
• 署名单位: University of Miami; State University System of Florida; University of Florida; Friedrich Schiller University of Jena; Tohoku University; Kyoto University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2524866123
• 发表日期: 2026-06-16
• 页码: e2524866123
• 关键词: GPCR; internalization; G proteins; GNAO1 disorder; G-BETA-GAMMA; binding; kinase; activation; PHOSDUCIN; phosphorylation; desensitization; mechanism; ARRESTIN; domain

摘要

G protein-coupled receptors (GPCRs) enable chemical communication between cells and are involved in nearly all essential functions. They transduce signals via heterotrimeric G proteins and are regulated by internalization, a process which redirects them from the cell surface to internal compartments and enables diversified signaling through spatial reorganization. Beyond the receptor, a vast regulatory network exists to further control G-protein signaling. However, it is unclear whether these modes of G-protein regulation also impact the upstream GPCR. Here, we systematically address how G-protein cycle regulation shapes GPCR internalization and establish several key principles and mechanisms governing this process. We find that timing of G-protein activation and deactivation and changes in G-protein cycle lifetime imparted by guanine nucleotide exchange factors, activators of G-protein signaling, and regulators of G-protein signaling can alter internalization outcomes. Furthermore, we determine how the activity and balance of discrete G-protein components interact with the G protein-coupled receptor kinase system to influence GPCR spatial distribution. Finally, we uncover that disease-associated variants of the most abundant G protein in the brain, G alpha oA, affect the regulatory network that drives GPCR internalization. Altogether, this study reveals that GPCR internalization is not a fixed receptor property but is dynamically governed by receptor-G-protein activation order, cycle lifetime, and the balance of G alpha and G beta gamma availability. As such, alterations in receptor internalization dynamics may contribute to the complex disease phenotypes associated with dysregulated G-protein networks.