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：
7342124
负责人：
LONNY R LEVIN
金额：
$ 36.75万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
https://reporter.nih.gov/project-details/7342124
关键词：
Adenylate Cyclase Alternative Splicing Applications Grants Bicarbonates Binding Biochemical Biochemical Genetics Brain Calcium Calcium ion Cell Line Cell membrane Coupled Cues Cyclic AMP Data Degenerative Disorder Development Family G-Protein-Coupled Receptors GTP-Binding Proteins Generations Goals Growth Growth Cones Growth Factor Heterotrimeric GTP-Binding Proteins Immunoprecipitation Ions Laboratories Learning Link Localized Mammalian Cell Mediating Mediator of activation protein Memory Methods Modeling Molecular Monomeric GTP-Binding Proteins Nerve Growth Factors Neuronal Differentiation Neurons Neurotransmitters Numbers PC12 Cells Pathway interactions Peptides Physiological Pituitary Gland Pituitary Hormones Production Property Protein Isoforms Proteins RNA Splicing Research Personnel Role Second Messenger Systems Signal Pathway Signal Transduction Small Interfering RNA Source Spinal Ganglia Testing Thinking adenylyl cyclase 1 axon growth axon regeneration axonal guidance genetic inhibitor human NTN1 protein inhibitor/antagonist member netrin-1 neuronal growth neurotrophic factor novel phosphodiesterase 6 programs receptor research study response retinal axon second messenger small 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 AMP (cAMP) 与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）通过 cAMP 与神经元分化、神经突发生和轴突再生相关。然而，它有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。轴突引导线索，例如 netrin-1，也通过 cAMP 发出信号，并且它们与第二信使生成的联系类似不清楚。此前，唯一已知的 cAMP 来源是 G 蛋白调节家族，跨膜腺苷酸环化酶（tmAC）； tmAC 介导 cAMP 变化以响应通过 G 蛋白偶联的七个跨膜受体发挥作用的神经递质。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，或者充其量是失败的事实证明是有争议的。我们的实验室鉴定了哺乳动物细胞中 cAMP 的独特来源，即“可溶性”腺苷酸环化酶 (sAC)。与 tmAC 相比，sAC 不受异源三聚体 G 蛋白调节，而是受碳酸氢根和钙离子。在此应用的初步结果中，我们证明 sAC 是负责响应神经营养蛋白 NGF 和轴突引导信号产生 cAMP netrin-1。我们已经鉴定出许多 sAC 的大脑亚型，它们与之前克隆的亚型不同，并且在本次资助申请中，我们建议表征这些新型脑 sAC 蛋白。我们还建议阐明 sAC 响应 NGF 和 netrin-1 激活机制的实验确定该信号级联是否被其他神经营养素和其他神经元利用回应。本拨款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号信息转化为神经元活动。这些研究对大脑发育具有重要意义退行性疾病以及学习和记忆。