Conservation of the ligand recognition site of metabotropic glutamate receptors during evolution

Mammalian metabotropic glutamate receptors (mGluRs) are classified into 3 g roups based on their sequence similarity and ligand recognition selectivity . Recently, we identified a Drosophila mGluR (DmGlu(A)R) which is about equ idistant, phylogenetically, from the 3 mGluR groups. However, both the G-pr otein coupling selectivity and the pharmacological profile of DmGlu(A)R, as analysed with mutated G-proteins and a few compounds, look similar to thos e 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 r at mGlu(1a), mGlu(2) and mGlu(4a) receptors, representative of group-I, II and III respectively. The pharmacological profile of DmClu(A)R was found to be similar to that of mGlu(2)R, and only very small differences could be i dentified at the level of their pharmacophore models. These data strongly s uggest that the binding sites of these two receptors are similar. To furthe r document this idea, a 3D model of the mGlu(2) binding domain was construc ted based on the low sequence similarity with periplasmic amino acid bindin g 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 gro up-II receptors. These data indicate that there has been a strong selective pressure during evolution to maintain the ligand recognition selectivity o f mGluRs. (C) 2000 Elsevier Science Ltd. All rights reserved.