Neuronal growth factor signaling via cAMP
通过 cAMP 的神经元生长因子信号传导
基本信息
- 批准号:7535181
- 负责人:
- 金额:$ 36.75万
- 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:2007-02-01 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adenylate CyclaseAlternative SplicingApplications GrantsBicarbonatesBindingBiochemicalBrainCalciumCalcium ionCell LineCell membraneCoupledCuesCyclic AMPDataDegenerative DisorderDevelopmentFamilyG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenerationsGeneticGoalsGrowthGrowth ConesGrowth FactorHeterotrimeric GTP-Binding ProteinsImmunoprecipitationIonsLaboratoriesLearningLinkMammalian CellMediatingMediator of activation proteinMemoryMethodsModelingMolecularMonomeric GTP-Binding ProteinsNerve Growth FactorsNeuronal DifferentiationNeuronsNeurotransmittersPC12 CellsPathway interactionsPeptidesPhysiologicalPituitary GlandPituitary HormonesProductionPropertyProtein IsoformsProteinsRNA SplicingResearch PersonnelRoleSecond Messenger SystemsSignal PathwaySignal TransductionSmall Interfering RNASourceSpinal GangliaTestingadenylyl cyclase 1axon growthaxon regenerationaxonal guidancegenetic inhibitorhuman NTN1 proteininhibitor/antagonistmembernetrin-1neuronal growthneurotrophic factornovelphosphodiesterase 6programsreceptorresearch studyresponseretinal axonsecond messengersmall molecule
项目摘要
In neurons, the ubiquitous second messenger cyclic AMP (cAMP) has been implicated in a number of
growth factor signaling pathways. For example, neurotrophins, such as Nerve Growth Factor (NGF), are
linked via cAMP to neuronal differentiation, neuritogenesis, and axonal regeneration. However, it has
remained unclear how to link the growth factors, or their receptors, to cAMP changes. Axonal guidance
cues, such as netrin-1, also signal via cAMP, and their link to second messenger generation is similarly
unclear. Previously, the only known source of cAMP had been the family of G protein regulated,
transmembrane adenylyl cyclases (tmACs); tmACs mediate the cAMP changes in response to
neurotransmitters which act via G protein coupled, seven transmembrane spanning receptors. But all
attempts to link tmACs to neuronal growth factor signals or axonal guidance cues have failed, or at best
proven controversial.
Our laboratory characterized a distinct source of cAMP in mammalian cells, 'soluble' adenylyl cyclase (sAC).
In contrast to tmACs, sAC is not modulated by heterotrimeric G proteins but is, instead, regulated by
bicarbonate and calcium ions. In preliminary results for this application, we demonstrate that sAC is
responsible for cAMP generation in response to both the neurotrophin NGF and the axonal guidance cue
netrin-1.
We have identified a number of brain isoforms of sAC which differ from the previously cloned isoforms, and
in this grant application, we propose to characterize these novel brain sAC proteins. We also propose
experiments to elucidate the mechanism of sAC activation in response to NGF and netrin-1 and to
determine whether this signaling cascade is utilized by other neurotrophins and in other neuronal
responses.
The hypotheses tested in this grant application will reveal how growth signals and guidance cues relay their
information into neuronal activity. These studies have important implications for brain development,
degenerative diseases and learning and memory.
在神经元中,普遍存在的第二信使环腺苷酸(cAMP)已被牵连在许多
生长因子信号通路。例如,神经营养因子,如神经生长因子(NGF),是神经营养因子的一种。
通过cAMP与神经元分化、轴突发生和轴突再生相关。但却
目前尚不清楚如何将生长因子或其受体与cAMP变化联系起来。轴突导向
提示,如netrin-1,也通过cAMP信号,它们与第二信使产生的联系类似
不清楚以前,cAMP的唯一已知来源是G蛋白调节家族,
跨膜腺苷酸环化酶(tmACs); tmACs介导cAMP的变化,
神经递质通过G蛋白偶联的七个跨膜受体起作用。但所有
将tmAC与神经元生长因子信号或轴突引导线索联系起来的尝试已经失败,或者充其量也是失败的
被证明是有争议的。
我们的实验室的特点是在哺乳动物细胞中的cAMP的一个独特的来源,'可溶性'腺苷酸环化酶(sAC)。
与tmAC相反,sAC不受异源三聚体G蛋白的调节,而是受
碳酸氢根和钙离子。在此应用程序的初步结果中,我们证明sAC是
负责响应神经营养因子NGF和轴突导向信号产生cAMP
netrin-1。
我们已经鉴定了许多sAC的脑同种型,它们不同于先前克隆的同种型,
在这个授权申请中,我们提出了表征这些新脑sAC蛋白。我们亦建议
阐明sAC激活响应于NGF和netrin-1以及
确定这种信号级联是否被其他神经营养因子和其他神经元细胞利用。
应答
在这项资助申请中测试的假设将揭示生长信号和指导线索如何传递它们的
信息转化为神经元活动。这些研究对大脑发育有重要意义,
退化性疾病和学习记忆
项目成果
期刊论文数量(0)
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{{ truncateString('LONNY R LEVIN', 18)}}的其他基金
Optimization of in vivo validated ADCY10 inhibitors
体内验证的 ADCY10 抑制剂的优化
- 批准号:
10747156 - 财政年份:2023
- 资助金额:
$ 36.75万 - 项目类别:
Neuronal growth factor signaling via cAMP
通过 cAMP 的神经元生长因子信号传导
- 批准号:
7342124 - 财政年份:2007
- 资助金额:
$ 36.75万 - 项目类别:
Neuronal growth factor signaling via cAMP
通过 cAMP 的神经元生长因子信号传导
- 批准号:
7194673 - 财政年份:2007
- 资助金额:
$ 36.75万 - 项目类别:
Neuronal growth factor signaling via cAMP
通过 cAMP 的神经元生长因子信号传导
- 批准号:
7738937 - 财政年份:2007
- 资助金额:
$ 36.75万 - 项目类别:
Neuronal growth factor signaling via cAMP
通过 cAMP 的神经元生长因子信号传导
- 批准号:
7935631 - 财政年份:2007
- 资助金额:
$ 36.75万 - 项目类别:
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