The metabotropic GABA receptor: molecular insights and their functional consequences

Recent years have seen rapid and significant advances in our understanding of the G-protein-coupled gamma-amino butyric acid, B-type (GABA,) receptor, which could be a therapeutic target in conditions as diverse as epilepsy a nd hypertension. This progress originated with the ground-breaking work of Bernhard Bettler's team at Novartis who cloned the DNA encoding a GABA(B) r eceptor in 1997. Currently, the receptor is thought to be an unusual, possi bly unique, example of a heterodimer composed of homologous, seven-transmem brane-domain (7TMD) subunits (named GABA(B) R1 and GABA(B) R2), neither of which is fully functional when expressed alone. The large N-terminal domain of the GABA(B) R1 subunit projects extracellularly and contains a ligand b inding site. The similarity of the amino acid sequence of this region to so me bacterial periplasmic amino acid-binding proteins of known structure has enabled structural and functional modelling of the N-terminal domain, and the identification of residues whose substitution modulates agonist/antagon ist binding affinities. The intracellular C-terminal domains of the R1 and R2 subunits appear to constitute an important means of contact between the two subunits. Alternative splice variants, a common and functionally import ant feature of 7TMD proteins, have been demonstrated for the R1 subunit. No tably GABA(B) R1a differs from GABA(B) R1b by the possession of an N-termin al extension containing two complement protein modules (also called SCRs, o r sushi domains) of unknown function. The levels at which each of the respe ctive variants is expressed are not equal to one another, with variations o ccurring over the course of development and throughout the central nervous system. It is not yet clear, however, whether one variant is predominantly presynaptically located and the other postsynaptically located. The existen ce of as yet unidentified splice variants, additional receptor subtypes and alternative quaternary composition has not been ruled out as a source of r eceptor heterogeneity.