Benzodiazepines modulate GABAA receptor surface levels and synaptic inhibition

苯二氮卓类药物调节 GABAA 受体表面水平和突触抑制

• 批准号: 7869700
• 负责人: Tija C. Jacob
• 金额: $ 8.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869700
• 关键词: 3-aminobutyric acid; Acute; Affect; Alcohols; Aminobutyric Acids; Anxiety; Automobile Driving; Benzodiazepine Receptor; Benzodiazepines; Biotinylation; Cell Surface Receptors; Cell membrane; Cell surface; Chronic Schizophrenia; Clathrin; Clinical; Complement; Control Animal; Data; Development; Down-Regulation; Drug Metabolic Detoxication; Endocytosis; Epilepsy; Excision; Exocytosis; Hippocampus (Brain); Hour; Image; In Vitro; Inhibitory Synapse; Life; Link; Measures; Mediating; Membrane Protein Traffic; Mental Depression; Molecular; Mus; Mutant Strains Mice; Neuraxis; Neurons; Neurotransmitter Receptor; Patients; Proteins; Proteolysis; Quality of life; Research; Role; Schizophrenia; Site; Sleeplessness; Slice; Structure; Substance abuse problem; Surface; Synapses; Testing; Therapeutic; Therapeutic Agents; Wild Type Mouse; efficacy testing; gamma-Aminobutyric Acid; improved; inhibitor/antagonist; novel therapeutics; public health relevance; receptor; research study; synaptic inhibition

DESCRIPTION (provided by applicant): Benzodiazepines are widely used to treat anxiety, insomnia and seizure disorders. Furthermore they are key adjunct treatments in schizophrenia, depression and alcohol detoxification. However, the use of these safe and efficacious compounds is severely limited due to the development of tolerance. Benzodiazepines potentiate the activity of 3-aminobutyric acid (GABAA) receptors, the major inhibitory neurotransmitter receptors in the central nervous system. The molecular mechanism underlying the development of tolerance has not yet been determined. It is increasingly evident that benzodiazepines preferentially enhance the activity of GABAA receptor subtypes present at synaptic sites that are largely composed of ?1-3, ? and ?2 subunits. In contrast, the majority of extrasynaptic GABAA receptors (GABAARs), which mediate tonic inhibition, have structures different from those of their synaptic counterparts and are insensitive to functional modulation by benzodiazepines. However, a mechanism linking benzodiazepine treatment of neurons to changes in surface levels of GABAAR subtypes and the efficacy of neuronal inhibition has not been demonstrated. These phenomena together with our preliminary studies generated the central hypothesis driving the experiments described in this proposal: Exposure of neurons to benzodiazepines promotes the removal of ?2 subunit-containing GABAARs from the plasma membrane and their subsequent degradation, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. Our proposal centers on three specific aims: (1) We will characterize the effects of benzodiazepine (BZ) treatment on GABAAR membrane trafficking and degradation; (2) We will measure the effects of BZ treatment on synaptic inhibition and identify the mechanism altering synaptic efficacy; and (3) We will measure the ability of BZ treatment to modulate cell surface accumulation of GABAARs and synaptic inhibition in wild type mice and ?2H101R mutant mice that express ?2-containing GABAAR that are BZ insensitive. PUBLIC HEALTH RELEVANCE: Benzodiazepines are widely used to treat anxiety, insomnia and seizure disorders, but their clinical use is severely limited due to the development of tolerance. The therapeutic actions of benzodiazepines are primarily exerted by potentiating the activity of ?-aminobutyric acid (GABA) type A receptors, the major inhibitory neurotransmitter receptors in the central nervous system. We will investigate the effects of benzodiazepines on GABA type A receptors to define a molecular mechanism underlying benzodiazepine tolerance, facilitating the development of new therapeutic agents to improve patient quality of life.

描述（由申请人提供）：苯二氮卓类药物广泛用于治疗焦虑、失眠和癫痫症。此外，它们是精神分裂症、抑郁症和酒精戒毒的关键辅助治疗。然而，由于耐受性的产生，这些安全有效的化合物的使用受到严重限制。苯二氮卓类药物可增强 3-氨基丁酸 (GABAA) 受体的活性，这是中枢神经系统中主要的抑制性神经递质受体。耐受性发展的分子机制尚未确定。越来越明显的是，苯二氮卓类药物优先增强突触位点上存在的 GABAA 受体亚型的活性，这些受体亚型主要由 ?1-3、?和β2亚基。相比之下，大多数介导强直抑制的突触外 GABAA 受体 (GABAAR) 具有与其突触对应物不同的结构，并且对苯二氮卓类药物的功能调节不敏感。然而，神经元苯二氮卓治疗与 GABAAR 亚型表面水平变化以及神经元抑制功效之间的联系机制尚未得到证实。这些现象与我们的初步研究一起产生了驱动本提案中描述的实验的中心假设：神经元暴露于苯二氮卓类药物会促进含有 ?2 亚基的 GABAAR 从质膜上去除并随后降解，从而导致抑制性突触减少大小和数量以及突触抑制功效的降低。我们的提案集中于三个具体目标：（1）我们将描述苯二氮卓（BZ）治疗对 GABAAR 膜运输和降解的影响； (2)我们将测量BZ治疗对突触抑制的影响并确定改变突触功效的机制； (3)我们将测量BZ处理调节野生型小鼠和表达含β2的GABAAR且对BZ不敏感的GABAAR的β2H101R突变小鼠的突触抑制的细胞表面积累和突触抑制的能力。 公共卫生相关性：苯二氮卓类药物广泛用于治疗焦虑、失眠和癫痫症，但由于耐受性的发展，其临床使用受到严重限制。苯二氮卓类药物的治疗作用主要是通过增强β-氨基丁酸（GABA）A型受体（中枢神经系统中主要的抑制性神经递质受体）的活性来发挥作用。我们将研究苯二氮卓类药物对 GABA A 型受体的影响，以确定苯二氮卓类药物耐受的分子机制，促进新治疗药物的开发，以改善患者的生活质量。