Recent advances in GABA(B) receptors: from pharmacology to molecular biology

Bicuculline-insensitive receptors for the inhibitory neurotransmitter gamma -aminobutyric acid (GABA), GABA(B) receptors, are a distinct subclass of re ceptors that mediate depression of synaptic transmission and contribute to neuronal inhibition. When activated, these receptors reduce transmission at excitatory and inhibitory synapses, as a result of an increase in K+ condu ctance, or a decrease in voltage-dependent Ca2+ currents. They are also lin ked to G-proteins, or intracellular effector systems in a very complex mann er. The recent development of highly specific and potent agonists and antag onists for these receptors has, led to a much better understanding of their physiology and pharmacology, including their heterogeneity, as well as the ir molecular biology. Over the past year, expression and cloning studies ha ve contributed to major advances in characterizing GABA(B) receptor structu re, with the discovery of the amino acid sequences of GABA(B)R1a/R1b splice variants and GABA(B)R2 receptors. These isoforms are widely distributed th roughout the nervous system, and can be functionally expressed. Importantly , GABA(B)R2 receptors can form a heteromeric assembly with GABA(B)R1 protei ns to operate as a heterodimer that displays robust coupling to inward-rect ifying K+ channels, as well as inhibition of forskolin- stimulated adenylat e cyclase activity. Further insights underlying the mechanisms of GABA(B) r eceptor functions can now be gained, leading ultimately to the therapeutic potential of drugs acting at these sites. It is increasingly clear that new information on GABA(B) receptor molecular structure will provide a plethor a of targets for pharmaceutical intervention in areas such as drug addictio n, nociception and absence seizures. This review summarizes the renewed eff orts, and highlights the recent advances emerging In this field.