ENDOPEPTIDASES AFFECT G-PROTEIN COUPLED RECEPTOR SIGNALING AND RESENSITIZATION
内肽酶影响 G 蛋白偶联受体信号传导和再敏化
基本信息
- 批准号:7724215
- 负责人:
- 金额:$ 0.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-06-01 至 2009-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgonistBig EndothelinBiologicalBradykininCell membraneCell surfaceComplexComputer Retrieval of Information on Scientific Projects DatabaseCoupledDegradation PathwayDiseaseDissociationEndocytosisEndopeptidasesEndosomesEndothelinEndothelin-1EnvironmentFamilyFunctional disorderFundingG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGrantHeterotrimeric GTP-Binding ProteinsHydrolysisIn VitroInflammationInstitutionMass Spectrum AnalysisNeprilysinNeuropeptidesPeptide HydrolasesProcessProteinsReceptor ActivationReceptor SignalingRecyclingResearchResearch PersonnelResourcesRoleSignal TransductionSorting - Cell MovementSourceSubstance PSubstance P ReceptorSubstrate SpecificityUnited States National Institutes of HealthVasoconstrictor Agentsdesensitizationendosome membranememberpreventreceptorreceptor recyclingresearch study
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
G-protein coupled receptor (GPCR) activation by neuropeptides is terminated by either cell-surface peptidase activity or receptor desensitization, and thereby prevents uncontrolled signaling that may cause dysfunction and disease. Cell-surface peptidases such as neutral endopeptidase (NEP) degrade extra-cellular neuropeptides and terminate their biological actions. For example, NEP degrades substance P (SP) and terminates inflammation by limiting the activation of the neurokinin-1 receptor (NK1R). Alternatively, activated GPCR signaling is terminated by desensitization, a process that entails uncoupling of heterotrimeric G-proteins and endocytosis of the receptor-agonist complex into endosomes where the acidic environment of the endosomes facilitates dissociation of the receptor and agonist. While the receptor is sorted to either recycling or degradative pathways by poorly understood mechanisms, the ultimate fate of the agonist after endocytosis is unknown.
Endothelin-converting enzyeme-1 (ECE-1) is a member of the M-13 family of endopeptidases that also includes NEP. While NEP is confined to the plasma membrane, ECE-1 has a broad subcellular distribution that includes both the plasma membrane and endosomes. The primary natural substrate of ECE-1 expressed at the plasma membrane is big endothelin (big-ET). Big-ET is hydrolyzed by ECE-1 at the plasma membrane to form endothelin-1 (ET), a potent vasoconstrictor. While ECE-1 hydrolyzes a variety of neuropeptides such as substance-P and bradykinin in in-vitro experiments, the biological significance of this activity is unknown. Furthermore, the role of ECE-1 contained in endosomes has not been explored.
The aim of this project is to study the role of ECE-1 in GPCR signaling. Activation of GPCRs results in endocytosis of the receptor and agonist into acidified endosomes. We propose that endopeptidases such as ECE-1 are also present in these acidified endosomes where they degrade the neuropeptide agonists and thereby control receptor recycling. Mass spectrometry will allow for characterization of endosomal ECE-1 activity and determine its substrate specificity.
这个子项目是许多研究子项目中的一个
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可以在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
神经肽对G蛋白偶联受体(GPCR)的激活可通过细胞表面肽酶活性或受体脱敏来终止,从而防止可能导致功能障碍和疾病的不受控制的信号传导。细胞表面肽酶如中性内肽酶(NEP)降解细胞外神经肽并终止其生物学作用。 例如,NEP降解P物质(SP)并通过限制神经激肽-1受体(NK 1 R)的激活来终止炎症。 或者,活化的GPCR信号传导通过脱敏终止,脱敏是一种需要异源三聚体G蛋白解偶联和受体-激动剂复合物内吞到内体中的过程,其中内体的酸性环境促进受体和激动剂的解离。 虽然受体通过知之甚少的机制被分类为再循环或降解途径,但内吞作用后激动剂的最终命运尚不清楚。
内皮素转化酶-1(ECE-1)是内肽酶M-13家族的成员,也包括NEP。 虽然NEP局限于质膜,但ECE-1具有广泛的亚细胞分布,包括质膜和内体。在质膜上表达的ECE-1的主要天然底物是大内皮素(big-ET)。 大ET在质膜上被ECE-1水解形成内皮素-1(ET),一种有效的血管收缩剂。 虽然ECE-1在体外实验中水解多种神经肽,如P物质和缓激肽,但这种活性的生物学意义尚不清楚。 此外,还没有探索内体中所含ECE-1的作用。
本项目的目的是研究ECE-1在GPCR信号转导中的作用。 GPCR的活化导致受体和激动剂内吞到酸化的内体中。 我们提出内肽酶如ECE-1也存在于这些酸化的内体中,在那里它们降解神经肽激动剂,从而控制受体再循环。 质谱法将允许表征内体ECE-1活性并确定其底物特异性。
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 }}
NIGEL W BUNNETT其他文献
NIGEL W BUNNETT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('NIGEL W BUNNETT', 18)}}的其他基金
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
10616927 - 财政年份:2022
- 资助金额:
$ 0.36万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
10174921 - 财政年份:2020
- 资助金额:
$ 0.36万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
10093340 - 财政年份:2020
- 资助金额:
$ 0.36万 - 项目类别:
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
10458307 - 财政年份:2020
- 资助金额:
$ 0.36万 - 项目类别:
Targeting Endosomal Receptors for Treatment of Chronic Pain
靶向内体受体治疗慢性疼痛
- 批准号:
9974866 - 财政年份:2020
- 资助金额:
$ 0.36万 - 项目类别:
Protease/PAR2/TRPV4 Axis and Oral Cancer Pain
蛋白酶/PAR2/TRPV4轴与口腔癌疼痛
- 批准号:
10020473 - 财政年份:2019
- 资助金额:
$ 0.36万 - 项目类别:
Protease/PAR2/TRPV4 Axis and Oral Cancer Pain
蛋白酶/PAR2/TRPV4轴与口腔癌疼痛
- 批准号:
10321672 - 财政年份:2018
- 资助金额:
$ 0.36万 - 项目类别:
Trafficking-Dependent Signaling of Pain by Protease-Activated Receptors
蛋白酶激活受体的贩运依赖性疼痛信号传导
- 批准号:
9757759 - 财政年份:2018
- 资助金额:
$ 0.36万 - 项目类别:
Endosomal Platforms for Neuropeptide Receptor Signaling
神经肽受体信号转导的内体平台
- 批准号:
10093292 - 财政年份:2017
- 资助金额:
$ 0.36万 - 项目类别:
相似国自然基金
Agonist-GPR119-Gs复合物的结构生物学研究
- 批准号:32000851
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
相似海外基金
S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
- 批准号:
24K12256 - 财政年份:2024
- 资助金额:
$ 0.36万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
- 批准号:
24K19176 - 财政年份:2024
- 资助金额:
$ 0.36万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
- 批准号:
10578068 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
- 批准号:
10650593 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
- 批准号:
10649275 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
- 批准号:
10734158 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
- 批准号:
10784209 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
- 批准号:
10580259 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
Identification and characterization of a plant growth promoter from wild plants: is this a novel plant hormone agonist?
野生植物中植物生长促进剂的鉴定和表征:这是一种新型植物激素激动剂吗?
- 批准号:
23K05057 - 财政年份:2023
- 资助金额:
$ 0.36万 - 项目类别:
Grant-in-Aid for Scientific Research (C)