Agonist-Induced Internalization and Degradation of γ-Aminobutyric AcidA (GABAA) Receptor Polypeptides from the Neuronal Surface
In the vertebrate brain, GABAA receptors on postsynaptic membranes are the major transducers of fast inhibitory neurotransmission. These receptors are hetero-pentameric proteins that provide specific binding sites for GABA, benzodiazepines, barbiturates, and anesthetic steroids as well as an integral chloride channel (Macdonald and Olsen, 1994). Chloride channel openings are gated by GABA and allosterically potentiated by benzodiazepines and other anxiolytic and hypnotic drugs. The exceptionally rich pharmacology associated with GABAA receptors has evoked considerable interest in their structure and function. Chronic administration of many GABAAergic compounds in humans and animals produces syndromes of dependence and tolerance which limit their clinical value. Since the development of tolerance to GABAAergic drugs is attributed to functional rather than pharmacokinetic accomodation (Greenblatt and Shader, 1986), attention has focused on use-dependent modifications of GABAA receptors. Indeed, there is general agreement that chronic exposure of rodents to benzodiazepines produces a decline in GABAA receptor function which coincides with the onset of tolerance (Miller et al., 1988; Marley and Gallager, 1989; Lewin et al., 1989). However, the molecular events which underlie this loss of receptor function are not well defined.
KeywordsGABAA Receptor Subunit mRNAs Neuronal Surface GABAA Receptor Function Receptor Polypeptide
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