GABA(B)-receptor subtypes assemble into functional heteromeric complexes

B-type receptors for the neurotransmitter GABA (gamma-aminobutyric acid) in hibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion ch annels and adenylyl cyclase(1). Physiological and biochemical studies show that there are differences in drug efficiencies at different GABA(B) recept ors, 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 GA BA(B)R1b), but native GABA(B) receptors and recombinant receptors showed un explained differences in agonist-binding potencies. Moreover, the activatio n of presumed effector ion channels in heterologous cells expressing the re combinant receptors proved difficult(3-4). Here we describe a new GABA(B) r eceptor subtype, GABA(B)R2, which does not bind available GABA(B) antagonis ts with measurable potency. GABA(B)R1a, GABA(B)R1b and GABA(B)R2 alone do n ot 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 lo calize together at dendritic spines. The heteromeric receptor complexes exh ibit a significant increase in agonist- and partial-agonist-binding potenci es as compared with individual receptors and probably represent the predomi nant native GABA(B) receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.