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Spatiotemporal dynamics of β-arrestin-mediated Src activation in 5-HT7 receptor signaling pathway

Hyunbin Kim1,2, Yong Woo Lee3, Huimin Lee1,4,5

  • 1Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.

The FEBS Journal
|March 14, 2026
PubMed

Insights

Biased ligands for the 5-hydroxytryptamine receptor 7 (5-HT7R) show differential effects in autism spectrum disorder models. A G protein-biased ligand induced ASD-like behavior, while a beta-arrestin-biased ligand activated Src kinase.

Area of Science:

  • Pharmacology
  • Neuroscience
  • Cell Biology

Background:

  • G protein-coupled receptors (GPCRs) mediate cellular signaling, with desensitization often involving beta-arrestin-dependent internalization.
  • Emerging evidence shows beta-arrestin also mediates G protein-independent pathways, leading to complex cellular responses.
  • GPCR-biased ligands selectively target these pathways, offering precise therapeutic control with fewer side effects.

Purpose of the Study:

  • To investigate the mechanisms of beta-arrestin-biased signaling for the 5-hydroxytryptamine receptor subtype 7 (5-HT7R).
  • To explore the role of 5-HT7R signaling in autism spectrum disorder (ASD) using biased ligands.
  • To elucidate the spatiotemporal regulation of Src activation in GPCR-biased signaling.

Main Methods:

  • Development and application of biased ligands for the 5-HT7R.
  • Assessment of ASD-like behaviors in mice following ligand administration.
  • Investigation of beta-arrestin-2 recruitment, Src kinase activation, and receptor complex internalization.
  • Analysis of Src colocalization with internalized receptor complexes at endosomes.

Main Results:

  • A G protein-biased 5-HT7R ligand induced ASD-like behavior in mice, unlike a beta-arrestin-biased ligand.
  • The beta-arrestin-biased ligand (1g) induced slow, sustained activation of proto-oncogene tyrosine-protein kinase Src (Src).
  • Src was recruited to 5-HT7R via beta-arrestin-2, leading to receptor internalization and sustained Src activation at endosomes.

Conclusions:

  • Beta-arrestin-biased 5-HT7R signaling exhibits temporal specificity, exemplified by sustained Src activation.
  • Spatiotemporal regulation of Src activation is a key mechanism in GPCR-biased signaling.
  • These findings offer novel insights for developing 5-HT7R-targeted therapeutics for ASD.
Keywords:
5‐HT7GPCR‐biased signalingserotoninsrcβ‐arrestin

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