THE G-PROTEIN-COUPLING PROFILE OF METABOTROPIC GLUTAMATE RECEPTORS, AS DETERMINED WITH EXOGENOUS G-PROTEINS, IS INDEPENDENT OF THEIR LIGANDRECOGNITION DOMAIN

Metabotropic glutamate (mGlu), Ca2+-sensing, gamma-aminobutyric acid(B ), and a large number of pheromone receptors constitute a peculiar fam ily of G protein-coupled receptors. They possess a large extracellular domain that has been proposed to constitute their ligand binding doma in. The aim of the current study was to examine whether this large lig and binding domain had any influence on the G protein-coupling selecti vity of the receptor, and vice versa. We chose mGlu receptors, which a re classified into three groups according to their sequence homology a nd pharmacology, as representatives of this receptor family. To define a G protein-coupling profile for these receptors, we used a set of ex ogenous phospholipase C-activating G proteins in the same way that syn thetic ligands are used to define agonist and antagonist pharmacologic al profiles. This set includes G(alpha 15), G(alpha 16), G(alpha q) an d chimeric G(alpha q) proteins with the last few amino acids of either G(alpha i2), (G(alpha qi)), G(alpha o) (G(alpha qo)), or G(alpha z) ( G(alpha qz)). Cotransfection of mGlu receptors with these G proteins a nd examination of their coupling to phospholipase C revealed that grou p I, II, and III receptors have distinct G protein-coupling profiles. By swapping the extracellular domains of the most distantly related mG lu receptors (the rat group I mGlu1a and the Drosophila melanogaster g roup II DmGluA receptors), we show that the extracellular domain deter mines the agonist pharmacological profile and that this domain does no t modify the G protein-coupling profile determined by the seven-transm embrane-domain region of mGlu receptors.