Functional competence of a partially engaged GPCR-β-arrestin complex

Nat Commun. 2016 Nov 9;7:13416. doi: 10.1038/ncomms13416.

Abstract

G Protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and drug targets. GPCR signalling and desensitization is critically regulated by β-arrestins (βarr). GPCR-βarr interaction is biphasic where the phosphorylated carboxyl terminus of GPCRs docks to the N-domain of βarr first and then seven transmembrane core of the receptor engages with βarr. It is currently unknown whether fully engaged GPCR-βarr complex is essential for functional outcomes or partially engaged complex can also be functionally competent. Here we assemble partially and fully engaged complexes of a chimeric β2V2R with βarr1, and discover that the core interaction is dispensable for receptor endocytosis, ERK MAP kinase binding and activation. Furthermore, we observe that carvedilol, a βarr biased ligand, does not promote detectable engagement between βarr1 and the receptor core. These findings uncover a previously unknown aspect of GPCR-βarr interaction and provide novel insights into GPCR signalling and regulatory paradigms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbazoles / pharmacology
  • Carvedilol
  • Endocytosis*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Phosphorylation
  • Propanolamines / pharmacology
  • Protein Binding / drug effects
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction*
  • beta-Arrestins / chemistry
  • beta-Arrestins / metabolism*

Substances

  • Carbazoles
  • Propanolamines
  • Receptors, G-Protein-Coupled
  • beta-Arrestins
  • Carvedilol