Characterization of the interaction between the dopamine D4 receptor, KLHL12 and β-arrestins

Kamila Skieterska, Ao Shen, Dorien Clarisse, Pieter Rondou, Dasiel Oscar Borroto-Escuela, Béatrice Lintermans, Kjell Fuxe, Yang Kevin Xiang, Kathleen Van Craenenbroeck

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Dopamine receptors are G protein-coupled receptors involved in regulation of cognition, learning, movement and endocrine signaling. The action of G protein-coupled receptors is highly regulated by multifunctional proteins, such as β-arrestins which can control receptor desensitization, ubiquitination and signaling. Previously, we have reported that β-arrestin 2 interacts with KLHL12, a BTB-Kelch protein which functions as an adaptor in a Cullin3-based E3 ligase complex and promotes ubiquitination of the dopamine D4 receptor.Here, we have investigated the molecular basis of the interaction between KLHL12 and β-arrestins and questioned its functional relevance. Our data demonstrate that β-arrestin 1 and β-arrestin 2 bind constitutively to the most common dopamine D4 receptor polymorphic variants and to KLHL12 and that all three proteins can interact within a single macromolecular complex. Surprisingly, stimulation of the receptor has no influence on the association between these proteins or their cellular distribution.We found that Cullin3 also interacts with both β-arrestins but has no influence on their ubiquitination. Knockout of one of the two β-arrestins hampers neither interaction between the dopamine D4 receptor and KLHL12, nor ubiquitination of the receptor.Finally, our results indicate that p44/42 MAPK phosphorylation, the signaling pathway which is often regulated by β-arrestins is not influenced by KLHL12, but seems to be exclusively mediated by Gαi protein upon dopamine D4 receptor stimulation.

Original languageEnglish (US)
Pages (from-to)1001-1014
Number of pages14
JournalCellular Signalling
Issue number8
StatePublished - Aug 1 2016


  • Dopamine D receptor
  • GPCR
  • KLHL12
  • Ubiquitination
  • β-arrestin

ASJC Scopus subject areas

  • Cell Biology


Dive into the research topics of 'Characterization of the interaction between the dopamine D<sub>4</sub> receptor, KLHL12 and β-arrestins'. Together they form a unique fingerprint.

Cite this