Molecular Identification of the Human GABA_BR2: Cell Surface Expression and Coupling to Adenylyl Cyclase in the Absence of GABA_BR1

Abstract

We have identified a gene encoding a GABA_Breceptor, the human GABA_BR2, located on chromosome 9q22.1, that is distinct from the recently reported rat GABA_BR1. GABA_BR2 structurally resembles GABA_BR1 (35% identity), having seven transmembrane domains and a large extracellular region, but differs in having a longer carboxy-terminal tail. GABA_BR2 is localized to the cell surface in transfected COS cells, and negatively couples to adenylyl cyclase in response to GABA, baclofen, and 3-aminopropyl(methyl)phosphinic acid in CHO cells lacking GABA_BR1. Baclofen action is inhibited by the GABA_BR antagonist, 2-hydroxysaclofen. The human GABA_BR2 and GABA_BR1 genes are differentially expressed in the nervous system, with the greatest difference being detected in the striatum in which GABA_BR1 but not GABA_BR2 mRNA transcripts are detected. GABA_BR2 and GABA_BR1 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum. Identification of a functional homomeric GABA_BR2 coupled to adenylyl cyclase suggests that the complexity of GABA_Bpharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms.