The identification of the molecular nature of the GABA(B) receptor and the demonstration of its heterodimeric structure has led to extensive studies investigating the mechanism of activation and signaling. Phylogenetic studies suggest that the formation of the heterodimer is a relatively recent event arising in conjunction with the evolution of the central nervous system. Heterodimerization has now been demonstrated for many other G-protein-coupled receptors (GPCRs) and plays a role in signaling and trafficking. This presents both challenges and opportunities for GPCR drug discovery. In the case of the GABA(B) receptor the best hope for the development of new drugs directed at this receptor is from allosteric modulators. This chapter summarizes our current understanding of the molecular function of the GABA(B) receptor and recent developments in the identification of allosteric modulators. The broader implication of heterodimerization on GPCR function and drug discovery is also discussed.
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