Lipid Regulation of Transient Receptor Potential Channels
瞬时受体电位通道的脂质调节
基本信息
- 批准号:7317216
- 负责人:
- 金额:$ 34.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-01 至 2012-05-31
- 项目状态:已结题
- 来源:
- 关键词:Afferent NeuronsBacteriaBiological ProcessCalcium ChannelCalcium SignalingCapsaicinCell membraneCellular MembraneComplexDataDependenceDetergentsExhibitsG-Protein-Coupled ReceptorsGoalsIon ChannelLipid BilayersLipidsMammalian CellMeasuresMediatingMembraneMentholMolecular BiologyNeuronsNociceptionPain managementPathway interactionsPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPhospholipidsPhosphoric Monoester HydrolasesPhysiologicalPlayPropertyProtein IsoformsProtein Kinase CProteinsReceptor Protein-Tyrosine KinasesRegulationRelative (related person)ResearchRoleRole playing therapySirolimusSystemTRPV1 geneTechniquesTemperatureTestingVesicleWorkbasecitrate carrierdesensitizationicilininhibitor/antagonistinsightnovelphosphatidylinositol phosphatereceptorreconstitutionresearch studytool
项目摘要
DESCRIPTION (provided by applicant): Phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate (Ptdlns(4,5)P2 or PIP2) regulate many if not all Transient Receptor Potential (TRP) channels. We will study the regulation of the cold-sensitive TRPM8 and the warmth-sensitive TRPV1 by phosphoinositides. We will focus on elucidating the mechanism and physiological importance of the regulation of these two channels by these lipids. TRPM8 and TRPV1 are expressed in sensory neurons and play important roles in thermosensation, as well as nociception. In Aim 1 we will study the regulation of TRPV1 by phosphoinositides. Our preliminary data and results from others indicate that PIP2 exerts dual control over TRPV1 channels, showing either inhibitory or stimulatory effects in certain settings. Our main hypothesis is that depletion of PIP2 (and PIP) by the activation of various PLC isoforms have differential effects on the channel, depending on the extent of depletion. To test this hypothesis we will combine novel and well established techniques in expression systems, as well as study TRPV1 in sensory neurons. In Aim 2 we will examine the physiological role of PIP2 in the regulation of TRPM8 currents. We have shown that PIP2 activates TRPM8 and that selective depletion of PIP2 is sufficient to inhibit these channels. Our hypothesis is that Ca2+ mediated activation of PLC and the ensuing depletion of PIP2 leads to desensitization of TRPM8 currents. TRPM8 is also inhibited by activators of protein kinase C (PKC), thus PKC mediated inhibition of TRPM8 may also underlie its desensitization. To elucidate the interplay between these two alternative mechanisms, and to define their relative contributions to desensitization, we will use the following approaches. We will test inhibitors and activators of PKC in conjunction with increasing or decreasing PIP2 using various tools, and measure TRPM8 desensitization. Experiments will be performed both in a mammalian expression system and native DRG neurons. In Aim 3 we will study the regulation of TRPM8 in a lipid bilayer system. The plasma membrane is a complex system consisting of a mixture of phospholipids and proteins, where we have limited tools to control the lipid composition of the membrane. Also, in a cellular membrane direct effects of regulatory molecules are hard to differentiate from indirect effects through other proteins. To overcome these limitations, we have purified the TRPM8 protein, incorporated it into planar lipid bilayers, and showed that it exhibits menthol-activated PIP2- dependent activity. We also reconstituted TRPM8 from mammalian cells expressing TRPM8, via native membrane vesicles. These systems allow full control of the phospholipid content of the membrane, therefore serves as a unique tool to study fundamental questions in lipid gating of TRPM8 channels that could not be answered with other techniques. Our data will provide mechanistic insight into the regulation of temperature sensitive TRP channel, and may also serve as a basis for better local pain control.
描述(申请人提供):磷脂酰肌醇4,5-二磷酸(Ptdlns(4,5)P2或PIP2)等磷脂酰肌醇调节许多(如果不是全部)瞬时受体电位(Trp)通道。我们将研究肌醇磷脂对冷敏性TRPM8和温敏性TRPV1的调节作用。我们将重点阐明这些脂类调节这两个通道的机制和生理意义。TRPM8和TRPV1在感觉神经元中表达,在体温感觉和伤害性感受中发挥重要作用。在目标1中,我们将研究肌醇磷脂对TRPV1的调节。我们的初步数据和其他人的结果表明,PIP2对TRPV1通道具有双重控制作用,在某些情况下表现出抑制或刺激作用。我们的主要假设是,不同PLC亚型激活的PIP2(和PIP)的耗竭对通道有不同的影响,这取决于耗竭的程度。为了验证这一假设,我们将结合新的和成熟的表达系统技术,以及研究感觉神经元中的TRPV1。在目标2中,我们将研究PIP2在调节TRPM8电流中的生理作用。我们已经证明,PIP2激活TRPM8,选择性地耗尽PIP2足以抑制这些通道。我们的假设是,钙离子介导的PLC激活和随后的PIP2耗竭导致TRPM8电流失敏。TRPM8也被蛋白激酶C(PKC)激活剂抑制,因此PKC介导的对TRPM8的抑制也可能是其脱敏的基础。为了阐明这两种替代机制之间的相互作用,并确定它们对脱敏的相对贡献,我们将使用以下方法。我们将使用各种工具测试PKC的抑制剂和激活剂,同时增加或减少PIP2,并测量TRPM8的脱敏作用。实验将在哺乳动物表达系统和天然背根神经节神经元中进行。在目标3中,我们将研究TRPM8在脂质双层系统中的调节。质膜是一个由磷脂和蛋白质的混合物组成的复杂系统,我们在控制膜脂组成方面的工具有限。此外,在细胞膜中,调节分子的直接作用很难与通过其他蛋白质的间接作用区分开来。为了克服这些限制,我们纯化了TRPM8蛋白,将其整合到平面脂质双层中,并表明它具有薄荷醇激活的PIP2依赖的活性。我们还通过天然的膜泡,从表达TRPM8的哺乳动物细胞中重组了TRPM8。这些系统允许完全控制膜的磷脂含量,因此是研究TRPM8通道脂质门控的基本问题的独特工具,这些问题是其他技术无法回答的。我们的数据将为温度敏感的Trp通道的调节提供机械性的见解,并可能作为更好的局部疼痛控制的基础。
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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Tibor Rohacs其他文献
Tibor Rohacs的其他文献
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{{ truncateString('Tibor Rohacs', 18)}}的其他基金
Regulation of the Intestinal Ca2+ Channels TRPV6
肠道 Ca2 通道 TRPV6 的调节
- 批准号:
8452114 - 财政年份:2011
- 资助金额:
$ 34.13万 - 项目类别:
Regulation of the Intestinal Ca2+ Channels TRPV6
肠道 Ca2 通道 TRPV6 的调节
- 批准号:
8634799 - 财政年份:2011
- 资助金额:
$ 34.13万 - 项目类别:
Regulation of the Intestinal Ca2+ Channels TRPV6
肠道 Ca2 通道 TRPV6 的调节
- 批准号:
8102559 - 财政年份:2011
- 资助金额:
$ 34.13万 - 项目类别:
Regulation of the Intestinal Ca2+ Channels TRPV6
肠道 Ca2 通道 TRPV6 的调节
- 批准号:
8244980 - 财政年份:2011
- 资助金额:
$ 34.13万 - 项目类别:
Regulation of the Intestinal Ca2+ Channels TRPV6
肠道 Ca2 通道 TRPV6 的调节
- 批准号:
8784840 - 财政年份:2011
- 资助金额:
$ 34.13万 - 项目类别:
Regulation of the Intestinal Ca2+ Channels TRPV6
肠道 Ca2 通道 TRPV6 的调节
- 批准号:
9275766 - 财政年份:2011
- 资助金额:
$ 34.13万 - 项目类别:
Lipid Regulation of Transient Receptor Potential Channels
瞬时受体电位通道的脂质调节
- 批准号:
7623470 - 财政年份:2007
- 资助金额:
$ 34.13万 - 项目类别:
Regulation of sensory TRP channels by phospholipids and G-proteins
磷脂和 G 蛋白对感觉 TRP 通道的调节
- 批准号:
10405595 - 财政年份:2007
- 资助金额:
$ 34.13万 - 项目类别:
Lipid Regulation of Transient Receptor Potential Channels
瞬时受体电位通道的脂质调节
- 批准号:
8581450 - 财政年份:2007
- 资助金额:
$ 34.13万 - 项目类别:
Regulation of sensory TRP channels by phospholipids and G-proteins
磷脂和 G 蛋白对感觉 TRP 通道的调节
- 批准号:
10166960 - 财政年份:2007
- 资助金额:
$ 34.13万 - 项目类别:
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