Recent advances in GABA receptor biology have resulted in elucidation of the molecular structure of a GABAB protein with similarity to metabotropic

Julia H. White Fiona H. Marshall 7TMReceptor Systems, Molecular Pharmacology Dept, GlaxoWellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire, UK SG1 2NY. Recent advances in GABA receptor biology have resulted in elucidation of the molecular structure of a GABAB protein with similarity to metabotropic glutamate receptors (mGluRs), GABAB(1) (Ref. 1), and the subsequent discovery by several laboratories that GABAB(1) heterodimerizes with GABAB(2) to form a functional G-protein-coupled receptor (GPCR) (Refs 2–7). For specific intervention in disorders such as epilepsy, pain and drug addiction, pharmacological subtypes would be therapeutically useful, and evidence from some pharmacological studies has indicated that subtypes do exist8. Since the initial cloning of GABAB(1a) and GABAB(1b), several other splice variants have emerged, in addition to splice variants of GABAB(2) (Refs 9–12). There is evidence to suggest GABAB(1a) and GABAB(1b) might represent preand postsynaptic subtypes, respectively, and evidence of functional heterogeneity has recently been published13. There are also indications that molecular subtypes might be pharmacologically distinguishable14. Investigation of structural determinants of ligand binding at GABAB receptors has indicated a venus flytrap model, with specific serine and glutamine mutations differentially affecting agonist and antagonist binding, and serine 269 being crucial for the Ca2+ sensitivity of the receptor15,16. Interestingly, although both mGluR4 and GABAB(2) can traffic GABAB(1) to the cell surface, only GABAB(2) and GABAB(1) can form a functional receptor 17. It would be surprising if physiologically relevant GABAB receptor subtypes did not occur, and studies on the nature of ligand binding and splice variants will undoubtedly advance the quest for subtypes, which could confer different physiological and pharmacological properties.