View the Current Issue

Article

  • The EMBO Journal (2006) 25, 3012 - 3023
  • doi:10.1038/sj.emboj.7601193

Published online: 15 June 2006

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

Angélique Levoye1,2,3,4, Julie Dam1,2,3,4, Mohammed A Ayoub1,2,3,4,a, Jean-Luc Guillaume1,2,3,4, Cyril Couturier1,2,3,4,b, Philippe Delagrange5 and Ralf Jockers1,2,3,4

  1. Department of Cell Biology, Institut Cochin, Paris, France
  2. Inserm U567, Paris, France
  3. CNRS, UMR 8104, Paris, France
  4. Université Paris 5, Faculté de Médecine René Descartes, UM 3, Paris, France
  5. Institut de Recherches SERVIER, Suresnes, France

Correspondence to:

Ralf Jockers, Institut Cochin, INSERM U567, CNRS 8104, Department of Cell Biology, 22 rue Méchain, Paris 75014, France. Tel.: +33 1 40 51 64 34; Fax: +33 1 40 51 64 30; E-mail: jockers@cochin.inserm.fr

aPresent address: Institut de Génomique Fonctionnelle, Département de Pharmacologie Moléculaire, CNRS-UMR 5203, INSERM U 661, Universités Montpellier 1 et 2, Montpellier, France

bPresent address: CNRS UMR 8090, Institut de Biologie de Lille—Institut Pasteur de Lille, Lille, France

Received 12 October 2005; Accepted 18 May 2006

One-third of the approx400 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 MT2 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.

  • Keywords:

    • GPCR,
    • melatonin,
    • melatonin-related receptor