Heterodimerization is required for the formation of a functional GABA B receptor

• Published in: Nature (London) Vol. 396; no. 6712; pp. 679 - 682
• Main Authors: Marshall, Fiona H, White, Julia H, Wise, Alan, Main, Martin J, Green, Andrew, Fraser, Neil J, Disney, Graham H, Barnes, Ashley A, Emson, Piers, Foord, Steven M
• Format: Journal Article
• Language: English
• Published: 17.12.1998
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/25354

GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABAA/C) receptors to produce fast synaptic inhibition and metabotropic (GABAB) receptors to produce slow, prolonged inhibitory signals. The gene encoding a GABAB receptor (GABABR1) has been cloned; however, when expressed in mammalian cells this receptor is retained as an immature glycoprotein on intracellular membranes and exhibits low affinity for agonists compared with the endogenous receptor on brain membranes. Here we report the cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABABR2), which we identified by mining expressed-sequence-tag databases. Yeast two-hybrid screening showed that this new GABABR2-receptor subtype forms heterodimers with GABABR1 through an interaction at their intracellular carboxy-terminal tails. Upon expression with GABABR2 in HEK293T cells, GABABR1 is terminally glycosylated and expressed at the cell surface. Co-expression of the two receptors produces a fully functional GABAB receptor at the cell surface; this receptor binds GABA with a high affinity equivalent to that of the endogenous brain receptor. These results indicate that, in vivo, functional brain GABAB receptors may be heterodimers composed of GABABR1 and GABABR2.