A NOVEL CLASS OF MAMMALIAN GABA RECEPTOR

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Neuronal inhibition is fundamental to brain function, and in vertebrates, the major inhibitory neurotransmitter is gamma-aminobutyric (GABA). Dysfunction of GABA-ergic systems appears to be involved in the development of numerous neurological and psychiatric diseases such as epilepsy, myoclonus, depression and anxiety, and might also play roles in Huntington's disease, schizophrenia and alcoholism. In mammals there are two well characterized families of GABA receptors. GABA-A receptors are ligand-gated Cl- channels, which are specifically antagonized by the convulsive alkaloid bicuculline. GABA-B receptors couple to GTP-binding proteins and intracellular messenger pathways, and are stereospecifically activated by (-)baclofen. GABA-A receptors appear to be the site which mediates actions of therapeutically useful drugs such as benzodiazepines and barbiturates, together with some of the sedative effects of alcohol. Drugs which selectively interact with GABA-B receptors are presently being developed, and could be of value in treating spasticity, seizure, and depression. Using RNA expression studies in frog oocytes, we have detected a novel class of mammalian GABA receptor, with pharmacological and electrical properties which clearly distinguish it from GABA-A or GABA-B. This receptor has high affinity for GABA, but is insensitive to both bicuculline and baclofen, and is not modulated by benzodiazepines or barbiturates. In view of the importance of other classes of GABA receptor in the CNS, we propose to characterize the structure, pharmacology and electrical properties of these novel GABA receptors. This will be a preliminary step in developing drugs which interact specifically with this site, and will provide a foundation for understanding the physiological roles played by bicuculline/baclofen-insensitive GABA receptors in mental function and health.