Regulation of G Protein-Coupled Receptors by Ubiquitination

Int J Mol Sci. 2017 Apr 27;18(5):923. doi: 10.3390/ijms18050923.


G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established. Furthermore, this modification can also play a role in targeting membrane and endoplasmic reticulum-associated receptors to the proteasome. Most recently, ubiquitination was also shown to be involved in GPCR signaling. In this review, we present current knowledge on the molecular basis of GPCR regulation by ubiquitination, and highlight the importance of E3 ubiquitin ligases, deubiquitinating enzymes and β-arrestins. Finally, we discuss classical and newly-discovered functions of ubiquitination in controlling GPCR activity.

Keywords: E3 ubiquitin ligase; G protein-coupled receptors (GPCR); deubiquitinating enzyme; ubiquitination; β-arrestin.

Publication types

  • Review

MeSH terms

  • Animals
  • Deubiquitinating Enzymes / metabolism
  • Humans
  • Lysosomes / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • beta-Arrestins / metabolism


  • Receptors, G-Protein-Coupled
  • beta-Arrestins
  • Ubiquitin-Protein Ligases
  • Deubiquitinating Enzymes
  • Proteasome Endopeptidase Complex