Related Experiment Video

Updated: Sep 19, 2025

Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
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Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay

Published on: March 10, 2020

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Interplay between G protein-biased and arrestin-biased pathways in 5-HT2AR-mediated ERK activation

Shujie Wang1, Dooti Kundu1, Lulu Peng1

  • 1Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.

Biochemical Pharmacology
|June 5, 2025
PubMed

Insights

G protein signaling is crucial for the arrestin-biased 5-HT2A receptor pathway, enabling ERK activation through nuclear ubiquitination of PKCβII and arrestin2. Arrestin2 is not required for G protein signaling, revealing a signaling hierarchy.

Area of Science:

  • Molecular pharmacology
  • Cellular signaling
  • Neuroscience

Background:

  • The 5-HT2A receptor (5-HT2A R) activates ERK through complex signaling pathways.
  • Understanding the interplay between G protein and arrestin signaling is key to receptor function.

Purpose of the Study:

  • To investigate the hierarchical relationship between G protein- and arrestin-biased signaling in 5-HT2A R-mediated ERK activation.
  • To elucidate the role of nuclear translocation and ubiquitination of PKCβII and arrestin2.

Main Methods:

  • Subcellular fractionation
  • shRNA-mediated knockdowns
  • Pharmacological inhibition
  • Wild-type and mutant arrestin2 and PKCβII constructs

Main Results:

  • 5-HT2A R stimulation triggers Mdm2-mediated nuclear ubiquitination of PKCβII and arrestin2, essential for ERK activation.
  • G protein signaling is required for the arrestin-biased pathway, but not vice versa.
  • Gq signaling promotes PKCβII nuclear entry, facilitating arrestin2 nuclear import and subsequent ubiquitination.

Conclusions:

  • G protein signaling is essential for initiating arrestin-mediated 5-HT2A R pathways.
  • A hierarchical signaling cascade exists where G protein pathways facilitate arrestin pathways.
Keywords:
5-HT(2A) receptorArrestinBiased signalingERKMdm2PKCβII

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