GABAB-receptor subtypes assemble into functional heteromeric complexes

B-type receptors for the neurotransmitter GABA (γ-aminobutyric acid) inhibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion channels and adenylyl cyclase 1 . Physiological and biochemical studies show that there are differences in drug efficiencies at different GABA B receptors, so it is expected that GABA B -receptor (GABA B R) subtypes exist 2 . Two GABA B -receptor splice variants have been cloned 3 (GABA B R1a and GABA B R1b), but native GABA B receptors and recombinant receptors showed unexplained differences in agonist-binding potencies. Moreover, the activation of presumed effector ion channels in heterologous cells expressing the recombinant receptors proved difficult 3 , 4 . Here we describe a new GABA B receptor subtype, GABA B R2, which does not bind available GABA B antagonists with measurable potency. GABA B R1a, GABA B R1b and GABA B R2 alone do not activate Kir3-type potassium channels efficiently, but co-expression of these receptors yields a robust coupling to activation of Kir3 channels. We provide evidence for the assembly of heteromeric GABA B receptors in vivo and show that GABA B R2 and GABA B R1a/b proteins immunoprecipitate and localize together at dendritic spines. The heteromeric receptor complexes exhibit a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors and probably represent the predominant native GABA B receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.