Molecular Physiology of Bicarbonate Transport in the Brain
大脑中碳酸氢盐运输的分子生理学
基本信息
- 批准号:8321009
- 负责人:
- 金额:$ 48.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1982
- 资助国家:美国
- 起止时间:1982-04-01 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acid-Base EquilibriumAcidsAffectAstrocytesAutistic DisorderBicarbonatesBindingBiological AssayBiological ModelsBlood - brain barrier anatomyBrainBreathingCalcineurinCell LineCell membraneCellsCerebrospinal FluidCoupledCytoplasmic ProteinDataDeletion MutationDetergentsDiseaseElectrophysiology (science)Endothelial CellsEnvironmental air flowEpilepsyExonsExtracellular FluidFamilyGenesGoalsHippocampus (Brain)IndividualInsectaIon ChannelKnock-outKnockout MiceLabelLibrariesMediatingMembraneMembrane ProteinsMemoryModificationMolecularMusNeuronsNeurotransmitter ReceptorOocytesPharmaceutical PreparationsPhysiologicalPhysiologyPlayPositioning AttributePropertyProtein BindingProtein phosphataseProteinsRNA SplicingRecombinant ProteinsRecombinantsRegulationResearchRespiratory AcidosisRoleScreening procedureSeizuresSiteSodium BicarbonateStructureStructure of choroid plexusSudden infant death syndromeSurface Plasmon ResonanceSynaptic TransmissionSystemTestingTissuesVariantWorkXenopus oocytebaseblindinsightneuronal excitabilitynovelprotein Bprotein phosphatase inhibitor-2receptorrespiratorysolid statetooltraffickinguptake
项目摘要
DESCRIPTION (provided by applicant): Electroneutral Na+coupled HCO-3 transporters (nNCBTs), in the SLC4 family, mediate - HCO3 uptake and (along with Na-H exchangers, NHEs) play important roles in regulating - the intracellular pH (pHi) of neurons. nNCBTs also contribute to HCO3 secretion by choroid plexus and blood-brain barrier endothelial cells. Thus, nNCBTs are in a position to have profound effects on ion channels and on neurotransmitter receptors and transporters, thereby influencing neuronal excitability and synaptic transmission. Preliminary data show that truncating an autoinhibitory domain (AID) from the cytosolic N terminus (Nt) of nNCBTs increases transport more than 2 fold. The cytoplasmic protein IRBIT-which binds to IP3 receptors and inhibits Ca release-also interacts with the Nt of nNCBTs, nullifying inhibition by the AID. A third protein, the phosphatase CnAB, appears to bind to the Nt of one of the nNCBTs and profoundly inhibit transport. These three players (AID, IRBIT, and CnAB) may be the most powerful known proteins controlling acid-base transport. Certain nNCBTs splice variants may lack the AID or binding domains for IRBIT or CnAB. The major goal of this proposal is to understand the control of nNCBTs by the AID and IRBIT (and also by CnAB), and how these interactions modulate neuronal function. The four aims: (1) Use functional assays in oocytes to elucidate the above interactions. (2) Use binding assays to detect the interactions. (3) Determine the contribution of the nNCBTs to pHi regulation in hippocampal (HC) vs. medullary-raphi (MR) neurons (some of which are chemosensitive), and the effect of pHi changes on electrophysiological parameters. This aim exploits mouse knockouts of the three nNCBTs as well as mice with fluorescent-labeled neurons to aid in identification. (4) To express, solubilize, and characterize several ancestral nNCBT proteins. The proposed work will clarify the molecular mechanism and regulation of the nNCBTs, and the role they play in neuronal function. The research could have important implications for understanding the control of ventilation, SIDS, seizure disorders, and perhaps autism.
描述(由申请人提供):slc4家族中的电负立Na+耦合HCO -3转运蛋白(NNCBTS),介导-HCO3摄取-HCO3摄取,(与Na -h -H交换器,NHES)在调节中起着重要作用 - 神经元的细胞内pH(PHI)。 NNCBT还有助于脉络丛和血脑屏障内皮细胞的HCO3分泌。因此,NNCBT可以对离子通道,神经递质受体和转运蛋白产生深远影响,从而影响神经元的兴奋性和突触传播。初步数据表明,NNCBTS的胞质N末端(NT)截断自身抑制域(AID)会增加运输超过2倍。细胞质蛋白IRBIT与IP3受体结合并抑制Ca释放与NNCBTS的NT相互作用,从而通过AID抑制了NNCBT的NT。第三个蛋白质磷酸酶CNAB似乎与其中一种NNCBT的NT结合并深刻抑制转运。这三个玩家(AID,IRBIT和CNAB)可能是控制酸碱运输的最强大的蛋白质。某些NNCBT剪接变体可能缺乏IRBIT或CNAB的辅助或结合域。该提案的主要目的是了解辅助和IRBIT(以及CNAB)对NNCBT的控制,以及这些相互作用如何调节神经元功能。这四个目的:(1)在卵母细胞中使用功能测定来阐明上述相互作用。 (2)使用绑定测定来检测相互作用。 (3)确定NNCBT对海马(HC)与髓质 - 拉斐(MR)神经元(其中一些是化学敏感)的贡献,以及PHI变化对电生理参数的影响。该目标利用了三个NNCBT的小鼠敲除以及具有荧光标记神经元的小鼠以帮助识别。 (4)表达,溶解和表征几种祖先NNCBT蛋白。提出的工作将阐明NNCBT的分子机制和调节,及其在神经元功能中的作用。这项研究可能对了解控制通风,小晶月,癫痫发作甚至自闭症具有重要意义。
项目成果
期刊论文数量(25)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Intracellular Cl- dependence of Na-H exchange in barnacle muscle fibers under normotonic and hypertonic conditions.
常渗和高渗条件下藤壶肌纤维中 Na-H 交换的细胞内 Cl 依赖性。
- DOI:10.1085/jgp.110.5.629
- 发表时间:1997
- 期刊:
- 影响因子:0
- 作者:Hogan,EM;Davis,BA;Boron,WF
- 通讯作者:Boron,WF
Expression and distribution of NBCn2 (Slc4a10) splice variants in mouse brain: cloning of novel variant NBCn2-D.
NBCn2 (Slc4a10) 剪接变体在小鼠大脑中的表达和分布:新变体 NBCn2-D 的克隆
- DOI:10.1016/j.brainres.2011.03.046
- 发表时间:2011-05-16
- 期刊:
- 影响因子:2.9
- 作者:Liu Y;Xu JY;Wang DK;Boron WF;Chen LM
- 通讯作者:Chen LM
K(+)- and HCO3(-)-dependent acid-base transport in squid giant axons II. Base influx.
鱿鱼巨轴突中 K( )- 和 HCO3(-) 依赖的酸碱运输 II。
- DOI:10.1085/jgp.106.5.845
- 发表时间:1995
- 期刊:
- 影响因子:0
- 作者:Hogan,EM;Cohen,MA;Boron,WF
- 通讯作者:Boron,WF
Cloning of a Na+-driven Cl/HCO3 exchanger from squid giant fiber lobe.
从鱿鱼巨型纤维叶中克隆 Na 驱动的 Cl/HCO3 交换器。
- DOI:10.1152/ajpcell.00439.2002
- 发表时间:2003
- 期刊:
- 影响因子:0
- 作者:Virkki,LeilaV;Choi,Inyeong;Davis,BruceA;Boron,WalterF
- 通讯作者:Boron,WalterF
Using fluorometry and ion-sensitive microelectrodes to study the functional expression of heterologously-expressed ion channels and transporters in Xenopus oocytes.
- DOI:10.1016/j.ymeth.2009.12.012
- 发表时间:2010-05
- 期刊:
- 影响因子:4.8
- 作者:Musa-Aziz, Raif;Boron, Walter F.;Parker, Mark D.
- 通讯作者:Parker, Mark D.
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Walter F Boron其他文献
Effects of optional structural elemements, including two alternative amino termini and a new splicing cassette IV, on the function of NBCn1 (SLC4A7)
可选结构元件(包括两个替代氨基末端和新剪接盒 IV)对 NBCn1 (SLC4A7) 功能的影响
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Harindarpal S Gill;Nathan Morris;Nathan Morris;Mark D Parker;Mark D Parker;Li-Ming Chen;Li-Ming Chen;Walter F Boron;Walter F Boron - 通讯作者:
Walter F Boron
Walter F Boron的其他文献
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{{ truncateString('Walter F Boron', 18)}}的其他基金
Mechanisms of oxygen off-loading from red blood cells in murine models of human disease
人类疾病小鼠模型中红细胞的氧卸载机制
- 批准号:
10343967 - 财政年份:2022
- 资助金额:
$ 48.69万 - 项目类别:
FAIR DOs: Findable, Accessible, Interoperable, Reusable Development of Open Simulation
FAIR DO:可查找、可访问、可互操作、可重用的开放模拟开发
- 批准号:
10523857 - 财政年份:2022
- 资助金额:
$ 48.69万 - 项目类别:
FAIR DOs: Findable, Accessible, Interoperable, Reusable Development of Open Simulation
FAIR DO:可查找、可访问、可互操作、可重用的开放模拟开发
- 批准号:
10707353 - 财政年份:2022
- 资助金额:
$ 48.69万 - 项目类别:
Mechanisms of oxygen off-loading from red blood cells in murine models of human disease
人类疾病小鼠模型中红细胞的氧卸载机制
- 批准号:
10548180 - 财政年份:2022
- 资助金额:
$ 48.69万 - 项目类别:
Molecular mechanism of Na+ -coupled HCO3- transporters: transport of CO3= and CO2
Na耦合HCO3-转运蛋白的分子机制:CO3=和CO2的转运
- 批准号:
10398247 - 财政年份:2021
- 资助金额:
$ 48.69万 - 项目类别:
Molecular mechanism of Na+ -coupled HCO3- transporters: transport of CO3= and CO2
Na耦合HCO3-转运蛋白的分子机制:CO3=和CO2的转运
- 批准号:
10187218 - 财政年份:2021
- 资助金额:
$ 48.69万 - 项目类别:
Cleveland Kidney, Urology and Hematology Training Network
克利夫兰肾脏、泌尿科和血液学培训网络
- 批准号:
10284382 - 财政年份:2021
- 资助金额:
$ 48.69万 - 项目类别:
Molecular mechanism of Na+ -coupled HCO3- transporters: transport of CO3= and CO2
Na耦合HCO3-转运蛋白的分子机制:CO3=和CO2的转运
- 批准号:
10640070 - 财政年份:2021
- 资助金额:
$ 48.69万 - 项目类别:
Cleveland Kidney, Urology and Hematology Training Network
克利夫兰肾脏、泌尿科和血液学培训网络
- 批准号:
10657715 - 财政年份:2021
- 资助金额:
$ 48.69万 - 项目类别:
Role of RPTP-gamma in sensing and transducing acid-base disturbances in the renal proximal tubule
RPTP-gamma 在肾近曲小管中传感和转导酸碱紊乱中的作用
- 批准号:
9926240 - 财政年份:2017
- 资助金额:
$ 48.69万 - 项目类别:
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