Regulation of chloride homeostasis and inhibitory synapses by palmitoylation
通过棕榈酰化调节氯稳态和抑制性突触
基本信息
- 批准号:8626454
- 负责人:
- 金额:$ 5.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:2-bromopalmitateAcuteAcyltransferaseAdultAffectAminobutyric AcidsBindingBiochemicalBiological AssayBiologyBiotinBrainCationsCell VolumesCell divisionCell surfaceCellsChloride IonChloridesChronicCo-ImmunoprecipitationsCysteineDevelopmentDiseaseDominant-Negative MutationEmbryonic DevelopmentEnzymesEpilepsyEquilibriumGene ExpressionHomeostasisInhibitory SynapseIschemiaLaboratoriesLigandsMediatingMembrane Protein TrafficMethodsMutationNeuritesNeuronsNeurotransmittersOsmolar ConcentrationPathogenesisPathologyPhosphorylationPost-Translational Protein ProcessingProcessProtein IsoformsProteinsRattusRegulationRelative (related person)ResearchRoleSignal TransductionSpecificityStagingTestingTimeWorkbrain tissuecell motilitychloride-cotransporter potassiumdesigngamma-Aminobutyric Acidin vivoinhibitor/antagonistinsightinterestneurotransmissionnovelnovel therapeuticspainful neuropathypalmitoylationpreventprotein degradationprotein expressionprotein functionprotein transportreceptorresearch studyresponsesensortherapeutic targettrafficking
项目摘要
DESCRIPTION (provided by applicant): The precise balance between excitatory and inhibitory neurotransmission is critical for healthy brain function. In the mature mammalian brain,
inhibitory signaling is predominantly accomplished through the neurotransmitter ¿-aminobutyric acid (GABA) binding to ligand-gated chloride (Cl-) channels (GABAA receptors). In contrast, in the immature brain GABAergic neurotransmission is excitatory in order to promote trophic activities necessary for development. The strength and polarity of GABA-mediated neurotransmission is determined by the intracellular chloride concentration. Changes in the relative activities of two chloride cotransporters, NKCC1 and KCC2, are responsible for the developmental switch in GABAergic signaling from excitatory to inhibitory. Importantly, disruptions in cellular chloride homeostasis resulting from dysfunctional NKCC1 and/or KCC2 activity result in neuronal hypo- or hyperexcitability that is implicated in the pathogenesis of epilepsy, chronic ischemia, and neuropathic pain. An understanding of the mechanisms responsible for regulating NKCC1 and KCC2 activity is lacking and is critical to the development of novel therapeutic strategies that target diseases resulting from altered Cl- homeostasis. While long-term differences in cotransporter activity are likely mediated by changes in gene expression, there is increasing evidence for acute regulation through post-translational modification and membrane trafficking. Protein palmitoylation is a reversible post-translational modification known to regulate various aspects of neuronal protein trafficking and function. The proposed research expands upon the preliminary finding that both NKCC1 and KCC2 are palmitoylated to test the hypothesis that palmitoylation regulates cotransporter activity either by
modulating their protein expression, maturation, oligomerization, phosphorylation, trafficking, and/or chloride transport. Inhibitor and mutational approaches to prevent cotransporter palmitoylation will be applied in various biochemical and cell biological assays to test the effect
of palmitoylation on cotransporter biology. To determine if developmental changes in cotransporter activity correlate with changes in palmitoylation, the acyl- biotin exchange (ABE) method, which was developed by our laboratory to quantitatively assess protein palmitoylation, will be used to characterize the palmitoylation of endogenous NKCC1 and KCC2 at various stages of brain development. Lastly, the ABE method in conjunction with knockdown and dominant negative approaches will be used to identify the enzymes responsible for mediating cotransporter palmitoylation. In summary, this work will explore a potentially novel mechanism for the regulation of NKCC1 and KCC2 activity and could provide insight into various pathologies that result from altered Cl- homeostasis as well as identify novel therapeutic strategies.
描述(申请人提供):兴奋性和抑制性神经传递之间的精确平衡对健康的大脑功能至关重要。在成熟哺乳动物的大脑中,
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sarah Elizabeth Antinone其他文献
Sarah Elizabeth Antinone的其他文献
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{{ truncateString('Sarah Elizabeth Antinone', 18)}}的其他基金
Regulation of chloride homeostasis and inhibitory synapses by palmitoylation
通过棕榈酰化调节氯稳态和抑制性突触
- 批准号:
8443558 - 财政年份:2012
- 资助金额:
$ 5.69万 - 项目类别:
Regulation of chloride homeostasis and inhibitory synapses by palmitoylation
通过棕榈酰化调节氯稳态和抑制性突触
- 批准号:
8316929 - 财政年份:2012
- 资助金额:
$ 5.69万 - 项目类别:
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