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作用及其功能障碍与几种形式的获得性癫痫有关。异源性Gabar亚基组成在确定受体的药理学和生理学中起作用。当使用毛car骨诱导成年大鼠的癫痫持续状态（SE）时，自发性癫痫发作（SS）随后发育，Gabar Alpha 1亚基mRNA水平降低。但是，当在P10诱导SE时，动物不会发展为SS，并且显示出Alpha 1亚基mRNA水平的增加。目前尚不清楚哪些因素有助于修改该亚基的表达，以及这种变化如何参与SS的发展。因此，研究被癫痫发作并调节α1亚基刺激的转录因子可能阐明了癫痫生成的这些机制。可以通过SE激活的CAMP响应元件结合蛋白（CREB）是调节转录因子的候选因子，因为Alpha One启动子包含其响应元件序列。这里提出的目的将研究：1）癫痫发作是否刺激CREB活性2）CREB与α1启动子结合3）不同的CREB激活途径影响Alpha一个mRNA水平。