The gamma-aminobutyric acid(B) (GABA(B)) receptor was first demonstrated on presynaptic terminals where it serves as an autoreceptor and also as a heteroreceptor to influence transmitter release by suppressing neuronal Ca(2+) conductance. Subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K(+) conductance and associated neuronal hyperpolarization. (-)-Baclofen is a highly selective agonist for GABA(B) receptors, whereas the established GABA(A) receptor antagonists, bicuculline and picrotoxin, do not block GABA(B) receptors. The receptor is G(i)/G(o) protein-coupled with mixed effects on adenylate cyclase activity. The receptor comprises a heterodimer with similar subunits currently designated 1 and 2. These subunits are coupled via coiled-coil domains at their C termini. The evidence for splice variants is critically reviewed. Thus far, no unique pharmacological or functional properties have been assigned to either subunit or the variants. The emergence of high-affinity antagonists for GABA(B) receptors has enabled a synaptic role to be established. However, the antagonists have generally failed to establish the existence of pharmacologically distinct receptor types within the GABA(B) receptor class. The advent of GABA(B1) knockout mice has also failed to provide support for multiple receptor types.

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In conclusion, GABAB receptors appear to be of major importance in synaptic processing within the brain and are present at both post- and presynaptic sites. Their activation can hyperpolarize neurones and diminish neurotransmitter release from presynaptic terminals. We already know that drugs, i.e. baclofen, that mimic this activation are therapeutically useful, although the full significance of their use both inside and outside the brain has yet to be realized. Drugs that interfere with GABAB receptor activation should also prove to be important therapeutic agents. A number of suggestions have been proposed but it will be many years before the potential effects can be consolidated or refuted in humans. Only now are brain-penetrating GABAB antagonists being discovered, due largely to the expertise of the research group at CIBA-Geigy, Basel. The emergence of such compounds makes future studies an exciting prospect. In particular, the discovery that GABAB antagonism can suppress absence seizures in rats has provided an important therapeutic target. It is now just over ten years since we first designated the term GABAB. Since then a wealth of information has been obtained, but perhaps the best is still to come.

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