Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA A receptor α4 subunit expression
| Autor: | D S, Roberts, Y H, Raol, S, Bandyopadhyay, I V, Lund, E C, Budreck, M A, Passini, M J, Passini, J H, Wolfe, A R, Brooks-Kayal, S J, Russek |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Transcription Genetic Protein subunit Molecular Sequence Data GABRA4 Hippocampal formation Epileptogenesis GABAA-rho receptor Interleukin 10 receptor alpha subunit Rats Sprague-Dawley Seizures Animals Humans RNA Messenger Promoter Regions Genetic Early Growth Response Protein 3 Cells Cultured Protein Kinase C Multidisciplinary Base Sequence biology GABAA receptor Dentate gyrus Brain Dependovirus Biological Sciences Receptors GABA-A Molecular biology Rats Up-Regulation DNA-Binding Proteins Protein Subunits nervous system biology.protein Sequence Alignment Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 102:11894-11899 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0501434102 |
| Popis: | GABA is the major inhibitory transmitter at CNS synapses. Changes in subunit composition of the pentameric GABA A receptor, including increased levels of α4 subunit in dentate granule cells and associated functional alterations such as increased zinc blockade of GABA currents, are hypothesized to be critical components of epileptogenesis. Here, we report that the minimal promoter of the human α4 subunit gene ( GABRA4p ), when used to drive reporter gene expression from adeno-associated viral vectors, controls condition-specific up-regulation in response to status epilepticus, defining a transcriptional mechanism for seizure-induced changes in levels of α4 subunit containing GABA A receptors. Transfection studies in primary hippocampal neurons show that inducible early growth response factor 3 (Egr3) up-regulates GABRA4p activity as well as the levels of endogenous α4 subunits. Given that Egr3 knockout mice display ≈50% less GABRA4 mRNAs in the hippocampus and that increases in α4 and Egr3 mRNAs in response to pilocarpine-induced status epilepticus are accompanied by increased binding of Egr3 to GABRA4 in dentate granule cells, our findings support a role for Egr3 as a major regulator of GABRA4 in developing neurons and in epilepsy. |
| Databáze: | OpenAIRE |
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