Use-Dependent Regulation of GabaA Receptors

摘要: Prolonged occupancy of GABAA receptors by ligands, including GABA and benzodiazepine agonists, sets in motion a series mechanisms that can be termed use-dependent regulation. These subdivided into two distinct pathways, one for receptor downregulation another upregulation. Treatment cortical neurons with or benzodiazepines cultures opens the pathway downregulation, which includes (in putative temporal order): (1) desensitization (tachyphylaxis), (2) sequestration (endocytosis) subunit polypeptides uncoupling allosteric interactions between binding sites, (3) polypeptide degradation, (4) repression gene expression. The end-point reduction number, is postulated to established initially degradation protein then maintained diminished level de novo synthesis. Benzodiazepine treatment many preparations, cells expressing recombinant receptors, may elicit only desensitization, sequestration, uncoupling, without decline number. Components are also evoked chronic administration GABAmimetics, benzodiazepines, barbiturates, neurosteroids animals. This correlates establishment tolerance physical dependence on pharmacological effects these drugs, suggesting cellular model this behavior. upregulation observed as neurotrophic actions GABA, primarily cultured cerebellar granule cells. Upregulation culture caused enhanced expression genes subunits GABAergic circuitry developing cerebellum. Thus, both appear represent pathways guiding synaptic plasticity vertebrate central nervous system.