Neuronal growth factor signaling via cAMP

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 如何将生长因子或其受体与cAMP变化联系起来仍不清楚。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 试图将tmAC与神经生长因子信号或轴突引导信号联系起来的尝试已经失败，或者充其量是失败， 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

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.