GABAB-receptor subtypes assemble into functional heteromeric complexes

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Abstract
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 cyclase1. Physiological and biochemical studies show that there are differences in drug efficiencies at different GABAB receptors, so it is expected that GABAB-receptor (GABABR) subtypes exist2. Two GABAB-receptor splice variants have been cloned3 (GABABR1a and GABABR1b), but native GABAB 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 difficult3,4. Here we describe a new GABAB receptor subtype, GABABR2, which does not bind available GABAB antagonists with measurable potency. GABABR1a, GABABR1b and GABABR2 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 GABAB receptors in vivo and show that GABABR2 and GABABR1a/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 GABAB receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.