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，普遍存在的第二信使环AMP （cAMP）参与了许多