1. Synaptic Pharmaceutical Corporation, 215 College Road, Paramus, New Jersey 07652, USA

Correspondence to: Kenneth A. Jones¹ Correspondence and request for materials should be addressed to K.A.J. (e-mail: Email: kjones@synapticcorp.com).The cDNA sequence for GABA_BR2 has been deposited at GenBank under accession number AF074482.

Abstract

The principal inhibitory neurotransmitter GABA (-aminobutyric acid) exerts its effects through two ligand-gated channels, GABA_A and GABA_C receptors, and a third receptor, GABA_B (ref. 1), which acts through G proteins to regulate potassium and calcium channels. Cells heterologously expressing the cloned DNA encoding the GABA_BR1 protein exhibit high-affinity antagonist-binding sites², but they produce little of the functional activity expected from studies of endogenous GABA_B receptors in the brain. Here we describe a new member of the GABA_B polypeptide family, GABA_BR2, that shows sequence homology to GABA_BR1. Neither GABA_BR1 nor GABA_BR2, when expressed individually, activates GIRK-type potassium channels; however, the combination of GABA_BR1 and GABA_BR2 confers robust stimulation of channel activity. Both genes are co-expressed in individual neurons, and both proteins co-localize in transfected cells. Moreover, immunoprecipitation experiments indicate that the two polypeptides associate with each other, probably as heterodimers. Several G-protein-coupled receptors (GPCRs) exist as high-molecular-weight species, consistent with the formation of dimers by these receptors^{3, 4, 5, 6, 7}, but the relevance of these species for the functioning of GPCRs has not been established. We have now shown that co-expression of two GPCR structures, GABA_BR1 and GABA_BR2, belonging to the samesubfamily is essential for signal transduction by GABA_B receptors.