Novel actions of neurosteroids on GABA (A) receptor trafficking

神经类固醇对 GABA (A) 受体运输的新作用

• 批准号: 8775257
• 负责人: Paul Andrew Davies
• 金额: $ 40.47万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775257
• 关键词: Address; Affinity; Aminobutyric Acids; Animals; Anxiety; Autistic Disorder; Barbiturates; Behavior; Benzodiazepines; Binding; Brain; Bungarotoxins; Cell Surface Receptors; Cell membrane; Cell surface; Corpus striatum structure; Data; Dependovirus; Development; Disease; Endocytosis; Epilepsy; Event; GABA-A Receptor; General anesthetic drugs; Goals; Health; Hippocampus (Brain); Intervention; Knockout Mice; Lead; Long-Term Effects; Measures; Mediating; Membrane; Membrane Protein Traffic; Membrane Proteins; Mental Depression; Microscopy; Modification; Neocortex; Neurons; Parahippocampal Gyrus; Pathway interactions; Phosphorylation; Play; Population; Premenstrual syndrome; Process; Protein Kinase C; Research; Role; Schizophrenia; Serine; Site; Slice; Stress; Substance abuse problem; Surface; Synapses; Testing; Thalamic structure; Time; Translating; anxiety treatment; comparative efficacy; dentate gyrus; gamma-Aminobutyric Acid; mutant; neuronal circuitry; neuronal excitability; neuropsychiatry; neurosteroids; neurotransmission; novel; novel therapeutic intervention; receptor; research study; residence; synaptic inhibition; trafficking

DESCRIPTION (provided by applicant): Tonic inhibition determines the excitability of neurons and the activity of neuronal circuits through the persistent activity of specialized populations of high affinity extrasynaptic γ-aminobutyric acid A receptors (GABAARs), that are the principle targets of neurosteroids. Neurosteroids are widely accepted as endogenous regulators of GABAergic inhibition. Fluctuations in the levels of neurosteroids are accepted to play a critical role in epilepsy, and are also relevant to autism, anxiety, depression, premenstrual syndrome and schizophrenia. However, to date, there is a fundamental gap in understanding how fluctuations in the levels of neurosteroids change extrasynaptic GABAAR subunit expression levels, which are a significant factor in the changes in GABAergic inhibition that occur in a plethora of neuropsychiatric disorders. Our long-term goal is to fully understand the mechanism by which neurosteroids influence the expression levels of extrasynaptic GABAARs. In this proposal we will address the role that neurosteroids play in protein kinase C (PKC)-dependent phosphorylation of α4 subunit-containing GABAARs. We will determine how this influences the cell surface accumulation of the GABAAR subtypes that mediate tonic inhibition. Our central hypothesis is that neurosteroids modulate the phosphorylation of GABAARs assembled from α4β3 and δ subunits, which mediate the majority of tonic inhibition in the dentate gyrus and thalamus. Neurosteroids specifically potentiate PKC-dependent phosphorylation of serine 443 (S443) in the α4 subunit. This increased phosphorylation leads to enhanced insertion of receptors composed of α4β3 and δ subunits into the plasma membrane that originate within the secretory pathway. These enhancements of receptor cell surface stability are responsible for sustained increases in the efficacy of tonic inhibition. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: (1) Determining the role of PKC-dependent phosphorylation in modulating the specific cell surface accumulation of GABAARs that mediate tonic inhibition (2) Visualizing neurosteroid- mediated changes in cell surface stability and membrane trafficking of GABAARs and (3) Ascertaining the effects of neurosteroid-dependent phosphorylation on the activity of GABAARs and the efficacy of tonic inhibition. In summary this proposal will demonstrate a new and unexpected mechanism by which neurosteroids exert persistent and sustained changes in the efficacy of tonic inhibition. Understanding neurosteroid-mediated changes in phosphorylation and cell surface expression of GABAARs has the potential to translate into better understanding of neuropsychiatric disorders. Moreover such information is likely to lead to the development of more efficacious treatments for anxiety, depression, premenstrual syndrome, schizophrenia and substance abuse.

描述（由申请人提供）：强直性抑制通过特定群体的持续活动来决定神经元的兴奋性和神经元回路的活动