GABAB-receptor subtypes assemble into functional heteromeric complexes

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 GABA_B receptors, so it is expected that GABA_B-receptor (GABA_BR) subtypes exist². Two GABA_B-receptor splice variants have been cloned³ (GABA_BR1a and GABA_BR1b), 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 difficult³,⁴. Here we describe a new GABA_B receptor subtype, GABA_BR2, which does not bind available GABA_B antagonists with measurable potency. GABA_BR1a, GABA_BR1b and GABA_BR2 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_BR2 and GABA_BR1a/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.