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

Nat Commun. 2017 Feb 9:8:14335. doi: 10.1038/ncomms14335.

Abstract

Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a β-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), stimulates acute catecholamine secretion through coupling with the transient receptor potential cation channel subfamily C 3 (TRPC3). We show that TRV120027 promotes the recruitment of TRPC3 or phosphoinositide-specific phospholipase C (PLCγ) to the AT1R-β-arrestin-1 signalling complex. Replacing the C-terminal region of β-arrestin-1 with its counterpart on β-arrestin-2 or using a specific TAT-P1 peptide to block the interaction between β-arrestin-1 and PLCγ abolishes TRV120027-induced TRPC3 activation. Taken together, our results show that the GPCR-arrestin complex initiates non-desensitized signalling at the plasma membrane by coupling with ion channels. This fast communication pathway might be a common mechanism of several cellular processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Catecholamines / metabolism*
  • Estrenes / pharmacology
  • HEK293 Cells
  • Humans
  • Ligands
  • Mice, Knockout
  • Oligopeptides / pharmacology
  • Phospholipase C gamma / metabolism
  • Pyrrolidinones / pharmacology
  • Receptor, Angiotensin, Type 1 / agonists*
  • Receptor, Angiotensin, Type 1 / metabolism
  • Signal Transduction / drug effects
  • TRPC Cation Channels / metabolism*
  • beta-Arrestin 1 / chemistry
  • beta-Arrestin 1 / metabolism*
  • beta-Arrestin 2 / metabolism*

Substances

  • Catecholamines
  • Estrenes
  • Ligands
  • Oligopeptides
  • Pyrrolidinones
  • Receptor, Angiotensin, Type 1
  • TRPC Cation Channels
  • TRPC3 cation channel
  • beta-Arrestin 1
  • beta-Arrestin 2
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Phospholipase C gamma
  • Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH
  • Calcium