Alternative mechanisms of signaling via trimeric G proteins
通过三聚体 G 蛋白传递信号的替代机制
基本信息
- 批准号:10374905
- 负责人:
- 金额:$ 47.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AchievementAdenylate CyclaseAffectAreaBindingBinding ProteinsBiological AssayBiosensorBrainBrain regionCell physiologyCellsChronic inflammatory painCoinCommunicationComplexCoupledCyclic AMPCytoplasmic ProteinDataDiseaseEnsureEpilepsyExcitatory SynapseFamilyG Protein-Coupled Receptor SignalingG-Protein Signaling PathwayG-Protein-Coupled ReceptorsGTP-Binding Protein RegulatorsGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGTPase-Activating ProteinsGeneticGoalsGrantGuanine Nucleotide Dissociation InhibitorsGuanosine TriphosphateHeterotrimeric GTP-Binding ProteinsHumanHydrolysisHyperalgesiaImpact SeizuresImpairmentIn VitroInhibitory SynapseIon ChannelKnockout MiceLaboratoriesLinkMapsMass Spectrum AnalysisMechanicsMediatingMediator of activation proteinMolecularNeuronsNeuropathyNeurotransmittersNucleotidesPainPatternPeripheral Nervous SystemPharmacologyPhysiologicalPhysiologyPopulationPost-Translational Protein ProcessingPredispositionProcessProteinsPublic HealthRGS ProteinsRegulationReportingRoleSeizuresSignal TransductionSignaling ProteinSiteSliceStimulusSynapsesTestingTherapeuticWild Type Mousebasechronic painhuman diseaseinsightmembermouse modelnervous system disorderneuroregulationneurotransmissionnovelprototypereceptorresponsespinal nerve posterior rootsynaptic function
项目摘要
SIGNIFICANCE: Our long-term goal is to discover novel regulatory components of a core mechanism of
cellular communication, i.e., signaling via heterotrimeric G proteins (henceforth trimeric G proteins), and to
characterize the molecular mechanisms that underlie their involvement in human disease. Our emphasis is on
cytoplasmic factors that regulate G protein signaling, which have been (and remain) understudied compared to
G protein-coupled receptors (GPCRs), the main activating inputs for trimeric G proteins. During the last grant
cycle, we made significant advances in this area by achieving all the originally proposed goals, thereby
establishing a new paradigm of G protein regulation. We demonstrated the existence of a family of cytoplasmic
activators of G proteins, dissected the structural basis for their molecular activity, and established the
consequences of their dysregulation in specific cellular processes and human diseases.
The specific goal of this renewal application is to characterize the prototype member of a potential new class of
G protein regulators that has been linked to chronic pain and epilepsy. The achievement of our goals would
provide deep mechanistic insights into a new paradigm of GPCR-G protein regulation that fine tunes inhibitory
neuromodulation, and establish a new framework to devise therapeutic strategies for neurological disorders
like chronic pain and epilepsy.
BACKGROUND: In the course of a screen of proteins that bind to Gαi subunits of Gα-Gβγ timeric complexes,
we identified a protein that regulates G proteins via a unique and novel mechanism. We have coined the term
“paradoxical G protein regulator” (PGR) to convey that it upregulates the modulation of some G protein
effectors while simultaneously downregulating the modulation of other G protein effectors. Loss of this “PGR” is
known to alter GPCR signaling in neurons of the peripheral nervous system and causes chronic pain. It has
also been linked to epilepsy. Despite its clear biomedical importance, the molecular mechanism by which this
G protein regulator operates, and how it modulates neurotransmission in the brain are completely unknown.
SYNOPSIS OF AIMS: Based on compelling preliminary data, we propose that the PGR modulates both Gαi-
and Gβγ-dependent signaling without directly affecting the G protein enzymatic activity (i.e., nucleotide binding
and/or hydrolysis), and that this novel mechanism fine tunes GPCR signaling in brain neurons to influence
seizure susceptibility. In Aim#1 we will dissect how the PGR regulates G proteins at the molecular level by
characterizing how it engages physically Gαi and the consequences of this physical engagement on G protein
signaling to different effectors. In Aim#2 we will characterize how it regulates GPCR signaling and
neurotransmission at the cellular level by using primary cultures of neurons and brain slices from wild-type and
KO mice. In Aim#3 we will determine the PGR's role at the physiological level by establishing how it impacts
seizure susceptibility using genetically modified mouse models.
意义:我们的长期目标是发现一个核心机制的新的调控成分,
蜂窝通信,即,通过异源三聚体G蛋白(下文称为三聚体G蛋白)进行信号传导,以及
描述其参与人类疾病的分子机制。我们的重点是
调节G蛋白信号传导的细胞质因子,与
G蛋白偶联受体(GPCR),三聚体G蛋白的主要激活输入。在上一次赠款期间
在这个周期中,我们通过实现所有最初提出的目标,在这一领域取得了重大进展,从而
建立了G蛋白调控的新范式。我们证明了存在一个家族的细胞质
G蛋白的激活剂,解剖了它们分子活性的结构基础,并建立了
它们在特定的细胞过程和人类疾病中失调的后果。
此更新应用程序的具体目标是表征潜在新类别的原型成员,
与慢性疼痛和癫痫有关的G蛋白调节剂。实现我们的目标将
提供了深入的机制洞察GPCR-G蛋白调控的新范式,微调抑制
神经调节,并建立一个新的框架,以制定治疗策略,神经系统疾病
比如慢性疼痛和癫痫
背景:在筛选与Gα-Gβγ亚基聚体复合物的Gαi亚基结合的蛋白质的过程中,
我们鉴定了一种通过独特和新颖的机制调节G蛋白的蛋白质。我们创造了一个术语
“矛盾的G蛋白调节因子”(PGR)来表达它上调某些G蛋白的调节
同时下调其他G蛋白效应子的调节。失去这个“PGR”是
已知改变外周神经系统神经元中的GPCR信号传导并引起慢性疼痛。它有
也与癫痫有关。尽管它具有明显的生物医学重要性,但其分子机制
G蛋白调节器的运作,以及它如何调节大脑中的神经传递是完全未知的。
目的概要:基于令人信服的初步数据,我们提出PGR调节Gαi-
和Gβγ依赖性信号传导而不直接影响G蛋白酶活性(即,核苷酸结合
和/或水解),并且这种新的机制微调了脑神经元中的GPCR信号传导,以影响
癫痫易感性在目标#1中,我们将通过以下方式剖析PGR如何在分子水平上调节G蛋白:
描述了它如何与Gαi发生物理接触,以及这种物理接触对G蛋白的影响。
向不同的效应器发出信号。在目标#2中,我们将描述它如何调节GPCR信号传导,
通过使用来自野生型的神经元和脑切片的原代培养物,
KO小鼠。在目标3中,我们将通过确定PGR如何影响
癫痫易感性的基因修饰小鼠模型。
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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Mikel Garcia-Marcos其他文献
Mikel Garcia-Marcos的其他文献
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{{ truncateString('Mikel Garcia-Marcos', 18)}}的其他基金
Versatile and high-fidelity optical biosensor platforms for GPCR signaling
用于 GPCR 信号传导的多功能高保真光学生物传感器平台
- 批准号:
10679863 - 财政年份:2023
- 资助金额:
$ 47.87万 - 项目类别:
Direct chemogenetic control of heterotrimeric G protein signaling
异源三聚体 G 蛋白信号传导的直接化学遗传学控制
- 批准号:
10590217 - 财政年份:2022
- 资助金额:
$ 47.87万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10220082 - 财政年份:2019
- 资助金额:
$ 47.87万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10461747 - 财政年份:2019
- 资助金额:
$ 47.87万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
9914590 - 财政年份:2019
- 资助金额:
$ 47.87万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10018921 - 财政年份:2019
- 资助金额:
$ 47.87万 - 项目类别:
Non-canonical activation of heterotrimeric G protein signaling in vivo
异源三聚体 G 蛋白信号传导的体内非典型激活
- 批准号:
10581960 - 财政年份:2019
- 资助金额:
$ 47.87万 - 项目类别:
Targeting of non-canonical G protein signaling with small molecules
用小分子靶向非经典 G 蛋白信号传导
- 批准号:
10180984 - 财政年份:2018
- 资助金额:
$ 47.87万 - 项目类别:
Next generation G protein activity biosensors
下一代 G 蛋白活性生物传感器
- 批准号:
9789949 - 财政年份:2018
- 资助金额:
$ 47.87万 - 项目类别:
Identification of chemical probes that specifically disrupt the GIV-Gi interface
鉴定特异性破坏 GIV-Gi 界面的化学探针
- 批准号:
8986801 - 财政年份:2015
- 资助金额:
$ 47.87万 - 项目类别:
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