Myosin VI drives arrestin-independent internalization and signaling of GPCRs

Patel, Nishaben M.; Ripoll, Léa; Peach, Chloe J.; Ma, Ning; Blythe, Emily E.; Vaidehi, Nagarajan; Bunnett, Nigel W.; von Zastrow, Mark; Sivaramakrishnan, Sivaraj

Abstract

G protein-coupled receptor (GPCR) endocytosis is canonically associated with β-arrestins. Here, we delineate a β-arrestin-independent endocytic pathway driven by the cytoskeletal motor, myosin VI. Myosin VI engages GIPC, an adaptor protein that binds a PDZ sequence motif present at the C-terminus of several GPCRs. Using the D2 dopamine receptor (D2R) as a prototype, we find that myosin VI regulates receptor endocytosis, spatiotemporal localization, and signaling. We find that access to the D2R C-tail for myosin VI-driven internalization is controlled by an interaction between the C-tail and the third intracellular loop of the receptor. Agonist efficacy, co-factors, and GIPC expression modulate this interaction to tune agonist trafficking. Myosin VI is differentially regulated by distinct GPCR C-tails, suggesting a mechanism to shape spatiotemporal signaling profiles in different ligand and physiological contexts. Our biophysical and structural insights may advance orthogonal therapeutic strategies for targeting GPCRs through cytoskeletal motor proteins.

Citation

Patel, N. M., Ripoll, L., Peach, C. J., Ma, N., Blythe, E. E., Vaidehi, N., Bunnett, N. W., von Zastrow, M., & Sivaramakrishnan, S. (2024). Myosin VI drives arrestin-independent internalization and signaling of GPCRs. Nature Communications, 15, Article 10636. https://doi.org/10.1038/s41467-024-55053-9

• Journal Article Type: Article
• Acceptance Date: Nov 26, 2024
• Online Publication Date: Dec 6, 2024
• Publication Date: Dec 6, 2024
• Deposit Date: Feb 20, 2025
• Publicly Available Date: Feb 21, 2025
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Article Number: 10636
• DOI: https://doi.org/10.1038/s41467-024-55053-9
• Public URL: https://nottingham-repository.worktribe.com/output/45596431
• Publisher URL: https://www.nature.com/articles/s41467-024-55053-9