GABAB2 Is Essential for G-Protein Coupling of the GABAB Receptor Heterodimer

Abstract

GABA_B receptors are unique among G-protein-coupled receptors (GPCRs) in their requirement for heterodimerization between two homologous subunits, GABA_B1and GABA_B2, for functional expression. Whereas GABA_B1 is capable of binding receptor agonists and antagonists, the role of each GABA_B subunit in receptor signaling is unknown. Here we identified amino acid residues 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 signal transduction through the second partner of a heteromeric complex.