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Updated: Jun 5, 2025

Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
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Myosin VI drives arrestin-independent internalization and signaling of GPCRs

Nishaben M Patel1, Léa Ripoll2, Chloe J Peach3,4

  • 1Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.

Nature Communications
|December 5, 2024
PubMed

Insights

A novel pathway for G protein-coupled receptor (GPCR) internalization involves myosin VI, independent of β-arrestins. This discovery reveals myosin VI

Area of Science:

  • Cell Biology
  • Molecular Pharmacology

Background:

  • G protein-coupled receptor (GPCR) endocytosis is primarily understood through β-arrestin-mediated pathways.
  • The role of cytoskeletal elements in GPCR trafficking and signaling remains an active area of investigation.

Purpose of the Study:

  • To identify and characterize a novel, β-arrestin-independent endocytic pathway for GPCRs.
  • To elucidate the mechanism by which the cytoskeletal motor myosin VI regulates GPCR internalization, localization, and signaling.

Main Methods:

  • Utilized the D2 dopamine receptor (D2R) as a model system.
  • Investigated the interaction between myosin VI, GIPC, and GPCR C-terminal motifs using biophysical and structural techniques.
  • Assessed the impact of myosin VI on receptor endocytosis, spatiotemporal localization, and signaling dynamics.

Main Results:

  • Identified a β-arrestin-independent endocytic pathway driven by myosin VI, involving the adaptor protein GIPC and a PDZ motif on GPCRs.
  • Demonstrated that myosin VI regulates D2R endocytosis, localization, and signaling.
  • Discovered that the accessibility of the D2R C-tail for myosin VI-mediated internalization is controlled by an intramolecular interaction, modulated by agonist efficacy, co-factors, and GIPC levels.
  • Showed differential regulation of myosin VI by various GPCR C-tails, suggesting context-specific signaling control.

Conclusions:

  • Myosin VI mediates a distinct GPCR endocytic pathway, offering new insights into receptor trafficking and spatiotemporal signaling.
  • The interaction between GPCR C-tails and intracellular loops provides a mechanism for fine-tuning receptor responses.
  • This pathway presents potential for developing novel therapeutic strategies targeting GPCRs via cytoskeletal motor proteins.

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