Heterodimerization is required for the formation of a functional GABAB receptor

Julia H. White, Alan Wise, Martin J. Main, Andrew Green, Neil J. Fraser, Graham H. Disney, Ashley A. Barnes, Piers Emson, Steven M. Foord and Fiona H. Marshall ()
Additional contact information
Julia H. White: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Alan Wise: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Martin J. Main: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Andrew Green: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Neil J. Fraser: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Graham H. Disney: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Ashley A. Barnes: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Piers Emson: Babraham Institute
Steven M. Foord: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre
Fiona H. Marshall: Receptor Systems, Molecular Pharmacology Unit, GlaxoWellcome, Medicines Research Centre

Nature, 1998, vol. 396, issue 6712, 679-682

Abstract: Abstract 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 cloned1; however, when expressed in mammalian cells this receptor is retained as an immature glycoprotein on intracellular membranes2 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.

Date: 1998
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DOI: 10.1038/25354

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