GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2

The principal inhibitory neurotransmitter GABA (gamma-aminobutyric acid) ex erts its effects through two ligand-gated channels, GABA(A) and GABA(C) rec eptors, and a third receptor, GABA(B) (ref. 1), which acts through G protei ns to regulate potassium and calcium channels. Cells heterologously express ing the cloned DNA. encoding the GABA(B)R1 protein exhibit high-affinity an tagonist-binding sites(2), but they produce little of the functional activi ty expected from studies of endogenous GABAB receptors in the brain. Here w e describe a new member of the GABA(B) polypeptide family, GABA(B)R2, that shows sequence homology to GABA(B)R1. Neither GABA(B)R1 nor GABA(B)R2, when expressed individually, activates GIRK-type potassium channels; however, t he combination of GABA(B)R1 and GABA(B)R2 confers robust stimulation of cha nnel activity. Both genes are co-expressed in individual neurons, and both proteins co-localize in transfected cells. Moreover, immunoprecipitation ex periments indicate that the two polypeptides associate with each other, pro bably as heterodimers. Several G-protein-coupled receptors (GPCRs) exist as high-molecutar-weight species, consistent with the formation of dimers by these receptors(3-7), but the relevance of these species for the functionin g of GPCRs has not been established We have now shown that co-expression of two GPCR structures, GABA(B)R1 and GABA(B)R2, belonging to the same subfam ily is essential for signal transduction by GABAB receptors.