Neuroproteomic mapping of kinases and their substrates downstream of acetylcholine: finding and implications.

IF 3.8 3区生物学 Q1 BIOCHEMICAL RESEARCH METHODS

Expert Review of Proteomics Pub Date : 2023-07-01 Epub Date: 2023-10-30 DOI:10.1080/14789450.2023.2265067

Yukie Yamahashi, Daisuke Tsuboi, Yasuhiro Funahashi, Kozo Kaibuchi

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引用次数: 0

Abstract

Introduction: Since the emergence of the cholinergic hypothesis of Alzheimer's disease (AD), acetylcholine has been viewed as a mediator of learning and memory. Donepezil improves AD-associated learning deficits and memory loss by recovering brain acetylcholine levels. However, it is associated with side effects due to global activation of acetylcholine receptors. Muscarinic acetylcholine receptor M1 (M1R), a key mediator of learning and memory, has been an alternative target. The importance of targeting a specific pathway downstream of M1R has recently been recognized. Elucidating signaling pathways beyond M1R that lead to learning and memory holds important clues for AD therapeutic strategies.

Areas covered: This review first summarizes the role of acetylcholine in aversive learning, one of the outputs used for preliminary AD drug screening. It then describes the phosphoproteomic approach focused on identifying acetylcholine intracellular signaling pathways leading to aversive learning. Finally, the intracellular mechanism of donepezil and its effect on learning and memory is discussed.

Expert opinion: The elucidation of signaling pathways beyond M1R by phosphoproteomic approach offers a platform for understanding the intracellular mechanism of AD drugs and for developing AD therapeutic strategies. Clarifying the molecular mechanism that links the identified acetylcholine signaling to AD pathophysiology will advance the development of AD therapeutic strategies.

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乙酰胆碱下游激酶及其底物的神经组织化学定位：发现和意义。

引言：自从阿尔茨海默病的胆碱能假说出现以来，乙酰胆碱一直被视为学习和记忆的媒介。多奈哌齐通过恢复大脑乙酰胆碱水平来改善AD相关的学习缺陷和记忆丧失。然而，由于乙酰胆碱受体的整体激活，它与副作用有关。毒蕈碱乙酰胆碱受体M1（M1R）是学习和记忆的关键介质，是另一种靶点。靶向M1R下游特定途径的重要性最近得到了认可。阐明M1R以外导致学习和记忆的信号通路为AD治疗策略提供了重要线索。涵盖的领域：这篇综述首先总结了乙酰胆碱在厌恶性学习中的作用，这是用于AD药物初步筛选的输出之一。然后描述了磷酸蛋白质组学方法，重点是识别导致厌恶性学习的乙酰胆碱细胞内信号通路。最后，讨论了多奈哌齐的细胞内作用机制及其对学习记忆的影响。专家意见：通过磷酸蛋白质组学方法阐明M1R以外的信号通路，为理解AD药物的细胞内机制和开发AD治疗策略提供了一个平台。阐明将已识别的乙酰胆碱信号传导与AD病理生理学联系起来的分子机制将推动AD治疗策略的发展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Expert Review of Proteomics 生物-生化研究方法

CiteScore

7.60

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Expert Review of Proteomics (ISSN 1478-9450) seeks to collect together technologies, methods and discoveries from the field of proteomics to advance scientific understanding of the many varied roles protein expression plays in human health and disease. The journal coverage includes, but is not limited to, overviews of specific technological advances in the development of protein arrays, interaction maps, data archives and biological assays, performance of new technologies and prospects for future drug discovery. The journal adopts the unique Expert Review article format, offering a complete overview of current thinking in a key technology area, research or clinical practice, augmented by the following sections: Expert Opinion - a personal view on the most effective or promising strategies and a clear perspective of future prospects within a realistic timescale Article highlights - an executive summary cutting to the author''s most critical points.