Use-dependent regulation of GABAA receptors

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