GABA(B2) is essential for G-protein coupling of the GABA(B) receptor heterodimer

GABA(B) receptors are unique among G-protein-coupled receptors (GPCRs) in t heir requirement for heterodimerization between two homologous subunits, GA BA(B1) and GABA(B2), for functional expression. Whereas GABA(B1) is capable of binding receptor agonists and antagonists, the role of each GABA(B) sub unit in receptor signaling is unknown. Here we identified amino acid residu es within the second intracellular domain of GABA(B2) that are critical for the coupling of GABA(B) receptor heterodimers to their downstream effector systems. Our results provide strong evidence for a functional role of the GABA(B2) subunit in G-protein coupling of the GABA(B) receptor heterodimer. In addition, they provide evidence for a novel "sequential" GPCR signaling mechanism in which ligand binding to one heterodimer subunit can induce si gnal transduction through the second partner of a heteromeric complex.