Abstract

The metabotropic glutamate receptors (mGluRs) are evolutionarily conserved from nematodes to vertebrates. The Caenorhabditis elegans (C. elegans) genome contains three mGluR genes referred to as mgl-1, mgl-2, and mgl-3. The aim of this study was to characterize the pharmacological profiles of orthosteric and allosteric mGluR ligands on mgl-2. A phylogenetic analysis revealed that mgl-2 is closely associated with the mammalian Group 1 mGluRs (mGluR1 and mGluR5) and is distinct from Group 2 and 3 mGluRs. The ligand binding domain of mgl-2 displayed higher homology to the rat Group 1 mGluRs binding domains compared to the level of homology in the heptahelical transmembrane domain regions. We found that, when transiently expressed in human embryonic kidney 293 cells, mgl-2 can be activated by glutamate and couples to human G-proteins to induce the release of intracellular calcium. Dose–response analyses revealed that mgl-2 has approximately a 15–20-fold lower affinity for glutamate and quisqualate compared to rat mGluR5. In contrast to orthosteric agonists, Group 1 negative allosteric modulators that target the transmembrane domain were ineffective at mgl-2. Surprisingly, CDPPB, an mGluR5 positive allosteric modulator, potentiated glutamate mediated activation of mgl-2, although MPEP and fenobam, two mGluR5 antagonists that share similar binding residues with CDPPB were ineffective at mgl-2. These findings indicate that selective pressures on mGluR protein structures have resulted in conservation of the glutamate binding site, whereas the allosteric modulator sites have been subjected to greater divergent evolutionary changes.

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