5-HT6 receptors: Contemporary views on their neurobiological and pharmacological relevance in neuropsychiatric disorders.

IF 8.3 2区 医学 Q1 Medicine
Dialogues in Clinical Neuroscience Pub Date : 2025-12-01 Epub Date: 2025-05-10 DOI:10.1080/19585969.2025.2502028
Abdeslam Chagraoui, Florence Thibaut, Philippe De Deurwaerdère
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引用次数: 0

Abstract

Despite the relatively limited number of serotonergic neurons in humans, serotonin plays a key role in neurophysiological functions, including sleep, pain perception, learning, memory, cognition, emotion, reward, and mood regulation. Altered serotonergic neurotransmission is linked to conditions such as anxiety, depression, anorexia, migraine, insomnia, schizophrenia, Alzheimer's disease (AD), and cognitive impairments. The 5-HT6 receptor (5-HT6R), mainly found in brain regions involved in cognition, is a promising therapeutic target for cognitive deficits in neuropsychiatric disorders, particularly AD and schizophrenia. Preclinical studies have shown that 5-HT6R antagonists improve cognitive function. 5-HT6R interacts dynamically with an extensive intracellular protein network, regulating the localisation, trafficking, and signalling of these proteins. Proteomic and genetic studies have revealed interactions with mTOR kinase and neurofibromin, both of which are crucial for synaptic plasticity, learning, and memory. Fyn kinase is also associated with 5-HT6Rs, reinforcing receptor expression and G-protein coupling. Notably, the G protein-regulated inducer of neurite outgrowth 1 (GPRIN1) interacts with 5-HT6Rs independently of agonists, enhancing receptor activity. This review highlights the clinical testing of 5-HT6R ligands as regulators of these complex signalling properties, underscoring their therapeutic potential in addressing cognitive impairments associated with neuropsychiatric disorders.

5-HT6受体:其在神经精神疾病中的神经生物学和药理学相关性的当代观点
尽管人体中血清素能神经元的数量相对有限,但血清素在神经生理功能中起着关键作用,包括睡眠、疼痛感知、学习、记忆、认知、情感、奖励和情绪调节。血清素能神经传递的改变与焦虑、抑郁、厌食症、偏头痛、失眠、精神分裂症、阿尔茨海默病(AD)和认知障碍等疾病有关。5-HT6受体(5-HT6R)主要存在于与认知相关的大脑区域,是治疗神经精神疾病,特别是阿尔茨海默病和精神分裂症认知缺陷的一个有希望的治疗靶点。临床前研究表明,5-HT6R拮抗剂可改善认知功能。5-HT6R与广泛的细胞内蛋白质网络动态相互作用,调节这些蛋白质的定位、运输和信号传导。蛋白质组学和遗传学研究揭示了与mTOR激酶和神经纤维蛋白的相互作用,两者对突触可塑性、学习和记忆都至关重要。Fyn激酶也与5-HT6Rs相关,加强受体表达和g蛋白偶联。值得注意的是,G蛋白调控的神经突生长诱导因子1 (GPRIN1)独立于激动剂与5-HT6Rs相互作用,增强受体活性。这篇综述强调了5-HT6R配体作为这些复杂信号特性调节剂的临床测试,强调了它们在解决与神经精神疾病相关的认知障碍方面的治疗潜力。
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来源期刊
Dialogues in Clinical Neuroscience
Dialogues in Clinical Neuroscience Medicine-Psychiatry and Mental Health
CiteScore
19.30
自引率
1.20%
发文量
1
期刊介绍: Dialogues in Clinical Neuroscience (DCNS) endeavors to bridge the gap between clinical neuropsychiatry and the neurosciences by offering state-of-the-art information and original insights into pertinent clinical, biological, and therapeutic aspects. As an open access journal, DCNS ensures accessibility to its content for all interested parties. Each issue is curated to include expert reviews, original articles, and brief reports, carefully selected to offer a comprehensive understanding of the evolving landscape in clinical neuroscience. Join us in advancing knowledge and fostering dialogue in this dynamic field.
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