Myosin VI drives arrestin-independent internalization and signaling of GPCRs

Nishaben M. Patel, Léa Ripoll, Chloe J. Peach, Ning Ma, Emily E. Blythe, Nagarajan Vaidehi, Nigel W. Bunnett, Mark von Zastrow and Sivaraj Sivaramakrishnan ()
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Nishaben M. Patel: University of Minnesota
Léa Ripoll: University of California, San Francisco
Chloe J. Peach: New York University
Ning Ma: Beckman Research Institute of the City of Hope
Emily E. Blythe: University of California, San Francisco
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope
Nigel W. Bunnett: New York University
Mark von Zastrow: University of California, San Francisco
Sivaraj Sivaramakrishnan: University of Minnesota

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-55053-9

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