GABA (g-amino butyric acid) is the most abundant neurotransmitter in mammalian brain. GABA, like other neurotransmitters, including L-glutamate, serotonin, and acetylcholine, activates both ionotropic and metabotropic receptors. The ionotropic receptors are ligand gated ion channels that convey fast synaptic transmission. In contrast, G-protein coupled metabotropic receptors modulate synaptic transmission through intracellular effector systems. The metabotropic receptors for L-glutamate (mGluRs) differ structurally from other G-coupled receptors with 7 TM domains. GABA exerts its effects through ionotropic ligand-gated GABAA, GABAC and GABAB to produce slow, and prolonged synaptic inhibitory signals by activating a Cl- conductance that is allosterically modulated by many psychoactive drugs, such as the benzodiazepines, barbiturates and neurosteroids. Presynaptic GABAB receptors (GABABRs) inhibit neurotransmitter release by down regulating high voltage activated, Ca+2 channels, whereas postsynaptic GABABRs decrease neuronal excitability by activating a prominent inwardly rectifying K+ (Kir) conductance that underlies the late inhibitory postsynaptic potential.

Two N-terminal splice variants GABABR1 (also called GBR1), GABABR1a (GBR1a, rat 960 aa, apparent mol wt ~130 kDa; human 961 aa) and GABABR1b (GBR1b; rat 844 aa, apparent mol. wt 100 kDa; human 844) have been cloned and characterized in rats and humans. Human and rat GBR1a and GBR1b share 99% sequence homology. GABABR1 receptors are characterized by the presence of a cleavable signal peptide, a large extracellular N-terminus, 7 TM domains, and Glu-rich, C-terminal, cytoplasmic domain. GABABRs also display a putative PDZ-domain interaction module, which may direct the assembly of signal transduction complex. The mature GBR1b differs from GBR1a in that the N-terminal 147 residues are replaced by 18 different residues. GBR1a and GBR1b share intracellular effector domains and ligand binding sites. The cloned GBR1a negatively couples to adenyl cyclase when expressed in HEK cells. Recombinant GBR1a and GBR1b protein have similar mol. wt and pharmacology to native receptors, and expressed in all major areas of the brain. Low level of GBR1a was also found in the heart.

Recently a new GABABR1 related receptor, termed GABABR2 (also known as GBR2) has been cloned and characterized from rat (940 aa) and human (941 aa). GBR2 has ~25% identity with GBR1a and ~30% with GBR1b. GBR2 expression is confined to the brain areas that are known to be rich in GABAB-receptor binding sites (hippocampus, medial habenula, thalamus, and cerebellum). GBR2 does not bind GABAB antagonist. Expression of neither GBR1 nor GBR2 alone produced a functional receptor. However, co-expression of these receptors produced a robust activation of Kir3-type K+-channel. Co-expression of GBR2 and GBR1 also produced glycosylated GBR1 that was transported to the cell surface. GBR1 and GBR2 immunoprecipitate and co-localize together at dendritic spines. GBR2 has also been shown to form heterodimer with GBR1 through interaction at the intracellular C-terminal tails. Therefore, native functional GABABRs may be heterodimeric.

ADI has produced antibodies to various GABABRs using isoform specific peptide sequences.