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: 8051550
• 负责人: Tija C. Jacob
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051550
• 关键词: 3-aminobutyric acid; Acute; Affect; Alcohols; Aminobutyric Acids; Anxiety; Anxiety Disorders; 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(申请人提供)：苯二氮卓类药物被广泛用于治疗焦虑、失眠和癫痫。此外，它们还是精神分裂症、抑郁症和戒酒的关键辅助治疗。然而，由于耐受性的发展，这些安全有效的化合物的使用受到了严重的限制。苯二氮卓类药物可增强3-氨基丁酸(GABAA)受体的活性，GABAA受体是中枢神经系统中主要的抑制性神经递质受体。耐受性形成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存在于突触部位的GABAA受体亚型的活性，这些亚型主要由？1-3，？和？2个亚基。相反，大多数介导紧张性抑制的突触外GABAA受体(GABAARs)的结构与它们的突触受体不同，对苯二氮类药物的功能调节不敏感。然而，苯二氮类药物对神经元的治疗与GABAAR亚型表面水平的变化以及神经元抑制的有效性之间的联系尚未得到证实。这些现象和我们的初步研究产生了驱动这一建议中描述的实验的中心假说：神经元暴露于苯二氮卓类药物促进含有β2亚单位的GABA受体从质膜上移除并随后降解，导致抑制性突触的大小和数量减少，突触抑制的有效性降低。我们的建议围绕三个具体目标：(1)我们将表征苯二氮(BZ)处理对GABAAR膜转运和降解的影响；(2)我们将测量BZ处理对突触抑制的影响，并确定改变突触效力的机制；以及(3)我们将检测BZ处理对野生型小鼠和？2H101R突变小鼠细胞表面GABAAR积累和突触抑制的调节能力(这些突触抑制表达含有BZ不敏感的？2-GABAAR)。 公共卫生相关性：苯二氮类药物被广泛用于治疗焦虑、失眠和癫痫障碍，但由于耐受性的发展，其临床应用受到严重限制。苯二氮卓类药物的治疗作用主要是通过增强中枢神经系统中主要的抑制性神经递质受体--氨基丁酸(GABA)A型受体的活性来实现的。我们将研究苯二氮类药物对GABA A型受体的影响，以确定苯二氮类药物耐受的分子机制，促进新的治疗药物的开发，以提高患者的生活质量。