title: Divergent evolution in metabotropic glutamate receptors. A new receptor activated by an endogenous ligand different from glutamate in insects.
abstract: The metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors involved in the regulation of glutamatergic synapses. Surprisingly, the evolution-arily distant Drosophila mGluR shares a very similar pharmacological profile with its mammalian orthologues (mGlu2R and mGlu3R). Such a conservation in ligand recognition indicates a strong selective pressure during evolution to maintain the ligand recognition selectivity of mGluRs and suggests that structural constraints within the ligand binding pocket (LBP) would hinder divergent evolution. Here we report the identification of a new receptor homologous to mGluRs found in Anopheles gambiae, Apis mellifera, and Drosophila melanogaster genomes and called AmXR, HBmXR, and DmXR, respectively (the mXRs group). Sequence comparison associated with three-dimensional modeling of the LBP revealed that the residues contacting the amino acid moiety of glutamate (the alpha-COO(-) and NH(3)(+) groups) were conserved in mXRs, whereas the residues interacting with the gamma-carboxylic group were not. This suggested that the mXRs evolved to recognize an amino acid different from glutamate. The Drosophila cDNA encoding DmXR was isolated and found to be insensitive to glutamate or any other standard amino acid. However, a chimeric receptor with the heptahelical and intracellular domains of DmXR coupled to G-protein. We found that the DmX receptor was activated by a ligand containing an amino group, which was extracted from Drosophila head and from other insects (Anopheles and Schistocerca). No orthologue of mXR could be detected in Caenorhabditis elegans or human genomes. These data indicate that the LBP of the mGluRs has diverged in insects to recognize a new ligand.
authors.affiliation: Laboratoire de Génomique Fonctionnelle, Unité Propre de Recherche 2580-CNRS, 141 Rue de la Cardonille, 34094 Montpellier Cedex 5, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Mitri
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Parmentier
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Yves
authors.initials: Y
authors.lastname: Grau
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004330:Drosophila; D019143:Evolution, Molecular; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid