Conservation of the ligand recognition site of metabotropic glutamate receptors during evolution.
Mammalian metabotropic glutamate receptors (mGluRs) are classified into 3 groups based on their sequence similarity and ligand recognition selectivity. Recently, we identified a Drosophila mGluR (DmGlu(A)R) which is about equidistant, phylogenetically, from the 3 mGluR groups. However, both the G-protein coupling selectivity and the pharmacological profile of DmGlu(A)R, as analysed with mutated G-proteins and a few compounds, look similar to those of mammalian group-II mGluRs. In the present study we carefully examined the pharmacological profile of DmGlu(A)R, and compared it to those of the rat mGlu(1a), mGlu(2) and mGlu(4a) receptors, representative of group-I, II and III respectively. The pharmacological profile of DmGlu(A)R was found to be similar to that of mGlu(2)R, and only very small differences could be identified at the level of their pharmacophore models. These data strongly suggest that the binding sites of these two receptors are similar. To further document this idea, a 3D model of the mGlu(2) binding domain was constructed based on the low sequence similarity with periplasmic amino acid binding proteins, and was used to identify the residues that possibly constitute the ligand recognition pocket. Interestingly, this putative binding pocket was found to be very well conserved between DmGlu(A)R and the mammalian group-II receptors. These data indicate that there has been a strong selective pressure during evolution to maintain the ligand recognition selectivity of mGluRs.
Parmentier
M L
ML
Centre INSERM-CNRS de Pharmacologie-Endocrinologie, UPR 9023-CNRS, rue de la Cardonille, 34094, Montpellier, France. parment@ccipe.montp.inserm.fr
Galvez
T
T
Acher
F
F
Peyre
B
B
Pellicciari
R
R
Grau
Y
Y
Bockaert
J
J
Pin
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005075:Biological Evolution; D002460:Cell Line; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D010802:Phylogeny; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007295:Inositol Phosphates; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate