Molecular identification of the human GABABR2:: Cell surface expression and coupling to adenylyl cyclase in the absence of GABABR1

We have identified a gene encoding a GABA(B) receptor, the human GABA(B)R2, located on chromosome 9q22.1, that is distinct from the recently reported rat GABA(B)R1. GABA(B)R2 structurally resembles GABA(B)R1 (35% identity), having seven transmembrane domains and a large extracellular region, but differs in having a longer carboxy-terminal tail. GABA(B)R2 is localized to the cell surface in transfected COS cells, and negatively couples to adenylyl cyclase in response to GABA, baclofen, and 8-aminopropyl(methyl)phosphinic acid in CHO cells lacking GABA(B)R1. Baclofen action is inhibited by the GABA(B)R antagonist, 2-hydroxysaclofen. The human GABA(B)R2 and GABA(B)R1 genes are differentially expressed in the nervous system, with the greatest difference being detected in the striatum in which GABA(B)R1 but not GABA(B)R2 mRNA transcripts are detected. GABA(B)R2 and GABA(B)R1 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum. Identification of a functional homomeric GABA(B)R2 coupled to adenylyl cyclase suggests that the complexity of GABA(B) pharmacological 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.