The heteromeric GABA-B receptor recognizes G-protein alpha subunit C-termini

The recently cloned GABA-B receptors are related to the metabotropic glutam ate receptors (mGlu receptors), the Ca2+-sensing receptor and one group of vomeronasal receptors. The GABA-B receptors likely function in a heterodime ric form, constituted of GABA-BR1 and GABA-BR2. This novel feature in the G -protein coupled receptors (GPCRs) structure raises questions as to the mec hanism of recognition of G-proteins by such receptors. In the present study we show that the GABA-BR1 and BR2 subunits form a functional receptor that recognizes the extreme C-termini of the G alpha i and G alpha o proteins w hen expressed in HEK293 cells. Indeed, heteromeric GABA-BR1/BR2 receptors d o not activate PLC when co-expressed with G alpha q, but do so when co-expr essed with the chimeric G alpha qi5 or G alpha qo5 subunits, the G alpha q subunit in which the 5 C-terminal residues are those of G alpha i or G alph a o, respectively. Interestingly, the heteromeric GABA-B receptor did not a ctivate the chimeric G alpha qz5 subunit that contains the 5 C-terminal res idues of G alpha z. Among the three residues that are distinct between G al pha qo5 and G alpha qz5 (at position - 5, - 4 and - 1), the amino acid resi due at position - 4 of G alpha o proteins is critical for specifying the co upling selectivity with the receptor and residue -5 influences the coupling efficacy. Interestingly, these findings correspond to data obtained with t he mGluR2 receptor, a distant relative of GABA-B proteins. This shows that the same molecular determinants of the G-protein alpha-subunits are involve d in the specific recognition of both the heteromeric GABA-B receptors and the other GPCRs. (C) 1999 Elsevier Science Ltd. All rights reserved.