The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization

Angélique Levoye, Julie Dam, Mohammed A. Ayoub, Jean Luc Guillaume, Cyril Couturier, Philippe Delagrange, Ralf Jockers

Research output: Contribution to journalArticlepeer-review

247 Citations (Scopus)

Abstract

One-third of the ∼400 nonodorant G protein-coupled receptors (GPCRs) are still orphans. Although a considerable number of these receptors are likely to transduce cellular signals in response to ligands that remain to be identified, they may also have ligand-independent functions. Several members of the GPCR family have been shown to modulate the function of other receptors through heterodimerization. We show that GPR50, an orphan GPCR, heterodimerizes constitutively and specifically with MT1 and MT2 melatonin receptors, using biochemical and biophysical approaches in intact cells. Whereas the association between GPR50 and MT2 did not modify MT 2 function, GPR50 abolished high-affinity agonist binding and G protein coupling to the MT1 protomer engaged in the heterodimer. Deletion of the large C-terminal tail of GPR50 suppressed the inhibitory effect of GPR50 on MT1 without affecting heterodimerization, indicating that this domain regulates the interaction of regulatory proteins to MT1. Pairing orphan GPCRs to potential heterodimerization partners might be of clinical importance and may become a general strategy to better understand the function of orphan GPCRs.

Original languageEnglish
Pages (from-to)3012-3023
Number of pages12
JournalEMBO Journal
Volume25
Issue number13
DOIs
Publication statusPublished - Jul 12 2006
Externally publishedYes

Keywords

  • GPCR
  • Melatonin
  • Melatonin-related receptor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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