Identification of a GABA(B) receptor subunit, gb2, required for functionalGABA(B) receptor activity

G protein-coupled receptors are commonly thought to bind their cognate liga nds and elicit functional responses primarily as monomeric receptors. In st udying the recombinant gamma-aminobutyric acid, type B (GABA,) receptor (gb 1a) and a GABA(B)-like orphan receptor (gb2), we observed that both recepto rs are functionally inactive when expressed individually in multiple hetero logous systems. Characterization of the tissue distribution of each of the receptors by in situ hybridization histochemistry in rat brain revealed co- localization of gb1 and gb2 transcripts in many brain regions, suggesting t he hypothesis that gb1 and gb2 may interact in vivo. In three established f unctional systems (inwardly rectifying K+ channel currents in Xenopus oocyt es, melanophore pigment aggregation, and direct cAMP measurements in HEK-29 3 cells), GABA mediated a functional response in cells coexpressing gb1a an d gb2 brit not in cells expressing either receptor individually. This GABA activity could be blocked with the GABA(B) receptor antagonist CGP71872, In COS-7 cells coexpressing gb1a and gb2 receptors, co-immunoprecipitation of gb1a and gb2 receptors was demonstrated, indicating that gb1a and gb2 act as subunits in the formation of a functional GABA(B) receptor.