CREB regulation of seizure induced GABAR subunit changes

CREB ​​对癫痫发作引起的 GABAR 亚基变化的调节

• 批准号: 7032990
• 负责人: Ingrid V Lund
• 金额: $ 4.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032990
• 关键词: GABA receptor; brain electrical activity; cAMP response element binding protein; disease /disorder etiology; disease /disorder model; electroencephalography; epilepsy; gene expression; generalized seizures; genetic promoter element; hippocampus; histology; immunoprecipitation; laboratory rat; messenger RNA; mitogen activated protein kinase; pilocarpine; predoctoral investigator; protein binding; protein kinase A; protein kinase C; protein structure function; scopolamine; transcription factor

DESCRIPTION (provided by applicant): The GABA A receptor (GABAR) mediates fast synaptic inhibition in the brain and its dysfunction is implicated in several forms of acquired epilepsy. Heteropentameric GABAR subunit composition plays a role in determining the pharmacology and physiology of the receptor. When pilocarpine is used to induce status epilepticus (SE) in adult rats, spontaneous seizures (SS) later develop and GABAR alpha 1 subunit mRNA levels decrease. However, when SE is induced at P10, animals do not develop SS and show increases in the alpha 1 subunit mRNA levels. It is unclear what factors contribute to modifying the expression of this subunit, and how this change is involved in the development of SS. Investigation into transcription factors that are stimulated by seizures and regulate the alpha 1 subunit may therefore elucidate these mechanisms of epileptogenesis. The cAMP response element binding protein (CREB), which may be activated by SE, is a candidate regulating transcription factor because the alpha one promoter contains its response element sequence. The aims proposed here will investigate whether: 1) seizures stimulate CREB activity 2) CREB binds to the alpha 1 promoter 3) different CREB activating pathways affect alpha one mRNA levels.

描述（由申请人提供）：GABA A 受体（GABAR）介导大脑中的快速突触抑制，其功能障碍与多种形式的获得性癫痫有关。异五聚体GABAR亚基组成在决定受体的药理学和生理学方面发挥作用。当毛果芸香碱用于诱导成年大鼠癫痫持续状态 (SE) 时，随后会出现自发性癫痫发作 (SS)，并且 GABAR α 1 亚基 mRNA 水平降低。然而，当在 P10 诱导 SE 时，动物不会出现 SS，并且显示 α1 亚基 mRNA 水平增加。目前尚不清楚哪些因素会改变该亚基的表达，以及这种变化如何参与 SS 的发展。因此，对癫痫发作刺激并调节 α1 亚基的转录因子的研究可能会阐明癫痫发生的这些机制。 cAMP 反应元件结合蛋白 (CREB) 可能被 SE 激活，是一种候选调节转录因子，因为 α1 启动子含有其反应元件序列。这里提出的目标将调查是否：1）癫痫发作刺激 CREB ​​活性 2）CREB ​​与 α 1 启动子结合 3）不同的 CREB ​​激活途径影响 α 1 mRNA 水平。