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
• 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
• 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/7194673
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：在神经元中，普遍存在的第二信使环磷酸腺苷（cAMP）与许多生长因子信号传导途径有关。例如，神经营养蛋白，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，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。轴突引导信号，例如 netrin-1，也通过 cAMP 发出信号，它们与第二信使生成的联系同样不清楚。此前，唯一已知的 cAMP 来源是 G 蛋白调节的跨膜腺苷酸环化酶 (tmAC) 家族。 tmAC 介导 cAMP 变化以响应神经递质，神经递质通过 G 蛋白偶联的七个跨膜受体发挥作用。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都失败了，或者充其量被证明是有争议的。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 不受异三聚体 G 蛋白调节，而是受碳酸氢根和钙离子调节。在该应用的初步结果中，我们证明 sAC 负责响应神经营养蛋白 NGF 和轴突引导信号 netrin-1 生成 cAMP。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，在本次拨款申请中，我们建议表征这些新型大脑 sAC 蛋白。我们还提出了实验来阐明 sAC 响应 NGF 和 netrin-1 激活的机制，并确定这种信号级联是否被其他神经营养素和其他神经元反应所利用。本次拨款申请中测试的假设将揭示生长信号和引导线索如何将其信息传递到神经元活动中。这些研究对大脑发育、退行性疾病以及学习和记忆具有重要意义。