Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling

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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

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Chun-Hua Liu1,2,3, Zheng Gong1, Zong-Lai Liang2

  • 1Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.

Nature Communications
|February 10, 2017
PubMed

Insights

G protein-coupled receptor (GPCR) signaling involves β-arrestins, which regulate hormone secretion. This study shows a specific GPCR agonist, TRV120027, uses β-arrestin-1 to activate TRPC3 ion channels, revealing a novel signaling pathway.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Physiology

Background:

  • G protein-coupled receptors (GPCRs) mediate crucial physiological responses through hormone secretion.
  • β-arrestins act as negative regulators of GPCR signaling and also initiate distinct intracellular pathways.
  • Understanding GPCR-mediated signaling is vital for numerous biological processes.

Purpose of the Study:

  • To investigate the mechanism by which TRV120027, a β-arrestin-1 biased agonist for the angiotensin II receptor type 1 (AT1R), stimulates catecholamine secretion.
  • To elucidate the role of TRPC3 channels and β-arrestin-1 in this signaling pathway.
  • To explore the interaction between GPCRs, β-arrestins, and ion channels in rapid cellular communication.

Main Methods:

  • Utilized TRV120027 as a β-arrestin-1 biased agonist for AT1R.
  • Investigated the recruitment of TRPC3 and phosphoinositide-specific phospholipase C (PLCγ) to the AT1R-β-arrestin-1 complex.
  • Employed genetic manipulation (replacing β-arrestin C-terminal regions) and peptide inhibition (TAT-P1) to block specific protein interactions.
  • Assessed TRPC3 channel activation in response to these manipulations.

Main Results:

  • TRV120027 directly stimulates acute catecholamine secretion.
  • TRV120027 promotes the recruitment of TRPC3 and PLCγ to the AT1R-β-arrestin-1 signaling complex.
  • Disruption of the β-arrestin-1/PLCγ interaction or alteration of β-arrestin structure abolished TRV120027-induced TRPC3 activation.
  • Demonstrated that the GPCR-arrestin complex can directly couple with ion channels at the plasma membrane.

Conclusions:

  • The GPCR-arrestin complex initiates rapid, non-desensitized signaling at the plasma membrane by coupling with ion channels, exemplified by AT1R-β-arrestin-1-TRPC3 interaction.
  • This pathway provides a novel mechanism for acute hormone secretion.
  • This fast communication pathway involving GPCRs, arrestins, and ion channels may represent a common cellular mechanism.

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