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
• 负责人: LONNY R LEVIN
• 金额: $ 1.01万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935631
• 关键词: Adenylate Cyclase; Alternative Splicing; Applications Grants; Bicarbonates; Binding; Biochemical; 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; Genetic; Goals; Growth; Growth Cones; Growth Factor; Heterotrimeric GTP-Binding Proteins; Immunoprecipitation; Ions; Laboratories; Learning; Link; Mammalian Cell; Mediating; Mediator of activation protein; Memory; Methods; Modeling; Molecular; Monomeric GTP-Binding Proteins; Nerve Growth Factors; Neuronal Differentiation; Neurons; Neurotransmitters; 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; 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

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，无处不在的第二信使循环放大器（CAMP）与许多 生长因子信号通路。例如，神经营养蛋白，例如神经生长因子（NGF），是 通过cAMP与神经元分化，神经发生和轴突再生有关。但是，它有 仍不清楚如何将生长因素或其受体与cAMP变化联系起来。轴突指导 Netrin-1等提示也通过CAMP发出信号，并且它们与第二信使的链接也同样是 不清楚。以前，唯一已知的CAMP来源是受调节的G蛋白家族， 跨膜腺苷酸环化酶（TMACS）； TMAC介导营地的变化，以响应 神经递质通过G蛋白耦合，七个跨膜跨受体。但是全部 试图将TMAC与神经元生长因子信号或轴突指导提示联系起来，或者充其量是 被证明是有争议的。 我们的实验室表征了哺乳动物细胞中cAMP的独特来源，即“可溶”腺苷酸环化酶（SAC）。 与TMAC相反，SAC不受异三聚体G蛋白的调节，而是由 碳酸氢盐和钙离子。在此应用程序的初步结果中，我们证明了SAC是 负责对神经营养蛋白NGF和轴突引导提示响应营地产生 Netrin-1。 我们已经确定了许多与先前克隆的同工型不同的SAC的大脑同工型，并且 在此赠款应用中，我们建议表征这些新型的脑囊蛋白。我们也建议 阐明响应NGF和Netrin-1的SAC激活机理的实验 确定该信号级联是否由其他神经营养蛋白和其他神经元使用 回答。 在本赠款申请中检验的假设将揭示增长信号和指导线索如何中继其 信息中的神经元活动。这些研究对大脑发育具有重要意义， 退化性疾病，学习和记忆。