| Autor: |
Patel, Nishaben M., Ripoll, Léa, Peach, Chloe J., Ma, Ning, Blythe, Emily E., Vaidehi, Nagarajan, Bunnett, Nigel W., von Zastrow, Mark, Sivaramakrishnan, Sivaraj |
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| Zdroj: |
Nature Communications; 12/6/2024, Vol. 15 Issue 1, p1-15, 15p |
| Abstrakt: |
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. G-protein coupled receptors (GPCRs) regulate numerous physiological processes and are a prominent therapeutic target. Here, Patel et al. delineate a β-arrestin independent pathway, driven by myosin VI, to shape GPCR trafficking and signaling. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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