Equipment Supplement: Sodium Channel Control of Neuronal Excitability
装备补充:钠通道控制神经元兴奋性
基本信息
- 批准号:10382711
- 负责人:
- 金额:$ 3.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsArrhythmiaBiochemicalBrainCalcium-Sensing ReceptorsDataDiseaseElectrophysiology (science)ElementsEquipmentG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGenerationsIon ChannelIon Channel GatingKnowledgeMeasuresMediatingMood DisordersMuscle CellsNerveNeurobiologyNeuronsPainPain managementParalysedPathway interactionsPeripheral Nervous System DiseasesPharmaceutical PreparationsPositioning AttributeProtein IsoformsProteinsRegulationSeizuresSignal PathwaySignal TransductionSodium ChannelSpasmTestingimprovedneocorticalneuronal cell bodyneuronal excitabilityneurotransmissionnew therapeutic targetnovelnovel therapeuticsreceptorside effectvoltage
项目摘要
PROJECT SUMMARY
Voltage-gated sodium channels (VGSCs) are essential for action potential generation. Furthermore, drugs that
directly target VGSCs are widely used to treat common diseases, such as pain, mood disorders, muscle
spasms, seizures, and cardiac arrhythmias. However, side effects arise because of the widespread distribution
of VGSCs and cross-sensitivity of the various VGSC subtypes to blockers. In addition, these drugs are not
completely effective, underlining a substantial need for new drugs that target VGSCs. This has motivated us to
identify and characterize new mechanisms by which VGSC function can be regulated. Regulation of voltage-
gated ion channel function is an important pathway by which neuronal signaling and brain function is regulated,
and G-protein coupled receptors (GPCRs) form a major element of the endogenous transduction mechanisms
by which this occurs. However, unlike other ion channels, VGSCs have been assumed to be relatively
insensitive to modulation by GPCR signaling. We have recently identified a pathway that is modulated by
agents known to interact with the CaSR (calcium-sensing receptor). This pathway is widespread, present in the
vast majority of neocortical neurons, and strong enough to completely and reversibly block VGSC currents
when maximally stimulated. This novel, dynamic signaling pathway is positioned to substantially modulate
neuronal excitability and brain function. Detailed knowledge about the underlying mechanisms is crucial to
understand its many effects. The objectives of this proposal are to determine how CaSR modulators regulate
VGSCs. Using a combination of electrophysiology and unbiased biochemical approaches we will identify the
receptors mediating the inhibition of VGSC currents, measure the relative sensitivity to block of different VGSC
isoforms, and determine if the pathway differentially regulates action potentials at nerve terminals and soma.
These specific aims will test the hypothesis that CaSR modulators actions via VGSCs represent important new
pathways for modulating neuronal excitability. We are ideally suited to perform this project because of our
preliminary data and expertise. Our rationale is that the identification and characterization of a novel and
prevalent receptor(s) and downstream pathway will facilitate our understanding of a prevalent and potentially
powerful neurobiological signaling pathway. Successful completion of these specific aims will characterize new
drug targets and eventually will lead to new therapeutics to improve control of pain, seizures, muscle spasm,
and arrhythmias.
项目总结
项目成果
期刊论文数量(0)
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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Stephen M Smith其他文献
Valproic acid and HIV-1 latency: beyond the sound bite
丙戊酸和 HIV-1 潜伏期:超越原话
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:3.3
- 作者:
Stephen M Smith - 通讯作者:
Stephen M Smith
Comprehensive Molecular Characterization of Polymorphous Adenocarcinoma, Cribriform Subtype: Identifying Novel Fusions and Fusion Partners.
多形性腺癌,筛状亚型的综合分子特征:识别新的融合和融合伴侣。
- DOI:
10.1016/j.modpat.2023.100305 - 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
E. Hahn;Bin Xu;N. Katabi;S. Dogan;Stephen M Smith;B. Perez–Ordoñez;Paras B. Patel;Christina MacMillan;Daniel J. Lubin;J. Gagan;I. Weinreb;J. Bishop - 通讯作者:
J. Bishop
New York City HIV superbug: fear or fear not?
纽约市艾滋病毒超级细菌:恐惧还是不恐惧?
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:3.3
- 作者:
Stephen M Smith - 通讯作者:
Stephen M Smith
Studying neuroanatomy using MRI
使用磁共振成像研究神经解剖学
- DOI:
10.1038/nn.4501 - 发表时间:
2017-02-23 - 期刊:
- 影响因子:20.000
- 作者:
Jason P Lerch;André J W van der Kouwe;Armin Raznahan;Tomáš Paus;Heidi Johansen-Berg;Karla L Miller;Stephen M Smith;Bruce Fischl;Stamatios N Sotiropoulos - 通讯作者:
Stamatios N Sotiropoulos
Stephen M Smith的其他文献
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{{ truncateString('Stephen M Smith', 18)}}的其他基金
Dynamic Chemical Regulation of Voltage-gated Sodium Channels
电压门控钠通道的动态化学调节
- 批准号:
10266071 - 财政年份:2015
- 资助金额:
$ 3.73万 - 项目类别:
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