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Frontiers in endocrinology
2021;12 714561.

Biased Coupling to β-Arrestin of Two Common Variants of the CB Cannabinoid Receptor.

Gábor Turu, Eszter Soltész-Katona, András Dávid Tóth, Cintia Juhász, Miklós Cserző, Ádám Misák, András Balla, Marc G Caron, László Hunyady
Author Information
  1. Gábor Turu: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  2. Eszter Soltész-Katona: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  3. András Dávid Tóth: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  4. Cintia Juhász: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  5. Miklós Cserző: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  6. Ádám Misák: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  7. András Balla: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  8. Marc G Caron: Department of Cell Biology, Duke University Medical Center, Duke University School of Medicine, Durham, NC, United States.
  9. László Hunyady: Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
PMID: 34484125 DOI: 10.3389/fendo.2021.714561

Abstract

β-arrestins are partners of the G protein-coupled receptors (GPCRs), regulating their intracellular trafficking and signaling. Development of biased GPCR agonists, selectively targeting either G protein or β-arrestin pathways, are in the focus of interest due to their therapeutic potential in different pathological conditions. The CB cannabinoid receptor (CBR) is a GPCR involved in various functions in the periphery and the central nervous system. Two common occurring variants of CBR, harboring Q63R or L133I missense mutations, have been implicated in the development of a diverse set of disorders. To evaluate the effect of these mutations, we characterized the binding profile of these mutant CB receptors to G proteins and β-arrestin2. Although their ability to inhibit cAMP signaling was similar, the Q63R mutant had increased, whereas the L133I mutant receptor had decreased β-arrestin2 binding. In line with these observations, the variants also had altered intracellular trafficking. Our results show that two common variants of the CB receptor have biased signaling properties, which may contribute to the pathogenesis of the associated disorders and may offer CBR as a target for further development of biased receptor activation strategies.

Keywords

CB2 cannabinoid receptor CB2R L133I Q63R biased polymorphisms signaling β-arrestin2

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MeSH Term

HEK293 Cells
Humans
Mutation, Missense
Protein Binding
Protein Transport
Receptor, Cannabinoid, CB2
beta-Arrestins

Chemicals

Receptor, Cannabinoid, CB2
beta-Arrestins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 4

Word Cloud

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