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种新的核心机制的调控成分
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Mikel Garcia-Marcos其他文献
Mikel Garcia-Marcos的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade
能量代谢的神经内分泌调节:垂体腺苷酸环化酶激活多肽(PACAP)在温度调节级联中的作用
- 批准号:
RGPIN-2021-04040 - 财政年份:2022
- 资助金额:
$ 47.87万 - 项目类别:
Discovery Grants Program - Individual
Controlled Release of Pituitary Adenylate Cyclase Activating Polypeptide from a Hydrogel-Nanoparticle Delivery Vehicle for Applications in the Central Nervous System
从水凝胶-纳米粒子递送载体中控制释放垂体腺苷酸环化酶激活多肽,用于中枢神经系统的应用
- 批准号:
547124-2020 - 财政年份:2022
- 资助金额:
$ 47.87万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Controlled Release of Pituitary Adenylate Cyclase Activating Polypeptide from a Hydrogel-Nanoparticle Delivery Vehicle for Applications in the Central Nervous System
从水凝胶-纳米粒子递送载体中控制释放垂体腺苷酸环化酶激活多肽,用于中枢神经系统的应用
- 批准号:
547124-2020 - 财政年份:2021
- 资助金额:
$ 47.87万 - 项目类别:
Postgraduate Scholarships - Doctoral
Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade
能量代谢的神经内分泌调节:垂体腺苷酸环化酶激活多肽(PACAP)在温度调节级联中的作用
- 批准号:
RGPIN-2021-04040 - 财政年份:2021
- 资助金额:
$ 47.87万 - 项目类别:
Discovery Grants Program - Individual
The Molecular Mechanism of the Secretion of the Bacterial Toxin Adenylate Cyclase
细菌毒素腺苷酸环化酶分泌的分子机制
- 批准号:
451966 - 财政年份:2021
- 资助金额:
$ 47.87万 - 项目类别:
Operating Grants
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
- 批准号:
10455587 - 财政年份:2020
- 资助金额:
$ 47.87万 - 项目类别:
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
- 批准号:
10261394 - 财政年份:2020
- 资助金额:
$ 47.87万 - 项目类别:
Diagnosis and therapeutic effect of neurally mediated syncope (NMS) using fluctuation of adenylate cyclase activity
利用腺苷酸环化酶活性波动对神经介导性晕厥(NMS)的诊断和治疗效果
- 批准号:
20K08498 - 财政年份:2020
- 资助金额:
$ 47.87万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pituitary adenylate cyclase-activating polypeptide 27 in the paraventricular thalamus and its projections: Role in ethanol drinking
室旁丘脑中的垂体腺苷酸环化酶激活多肽 27 及其预测:在乙醇饮用中的作用
- 批准号:
10380126 - 财政年份:2020
- 资助金额:
$ 47.87万 - 项目类别:
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
- 批准号:
10662279 - 财政年份:2020
- 资助金额:
$ 47.87万 - 项目类别:














{{item.name}}会员




