Sarkar Parijat, Mozumder Sukanya, Bej Aritra, Mukherjee Sujoy, Sengupta Jayati, Chattopadhyay Amitabha
CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India.
Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700 032, India.
Biophys Rev. 2020 Nov 14;13(1):101-22. doi: 10.1007/s12551-020-00772-8.
Serotonin (5-hydroxytryptamine, 5-HT) is an intrinsically fluorescent neurotransmitter found in organisms spanning a wide evolutionary range. Serotonin exerts its diverse actions by binding to distinct cell membrane receptors which are classified into many groups. Serotonin receptors are involved in regulating a diverse array of physiological signaling pathways and belong to the family of either G protein-coupled receptors (GPCRs) or ligand-gated ion channels. Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive and behavioral functions such as sleep, mood, pain, anxiety, depression, aggression, and learning. Serotonin receptors act as drug targets for a number of diseases, particularly neuropsychiatric disorders. The signaling mechanism and efficiency of serotonin receptors depend on their amazing ability to rapidly access multiple conformational states. This conformational plasticity, necessary for the wide variety of functions displayed by serotonin receptors, is regulated by binding to various ligands. In this review, we provide a succinct overview of recent developments in generating and analyzing high-resolution structures of serotonin receptors obtained using crystallography and cryo-electron microscopy. Capturing structures of distinct conformational states is crucial for understanding the mechanism of action of these receptors, which could provide important insight for rational drug design targeting serotonin receptors. We further provide emerging information and insight from studies on interactions of membrane lipids (such as cholesterol) with serotonin receptors. We envision that a judicious combination of analysis of high-resolution structures and receptor-lipid interaction would allow a comprehensive understanding of GPCR structure, function and dynamics, thereby leading to efficient drug discovery.
血清素（5-羟色胺，5-HT）是一种具有内在荧光的神经递质，存在于广泛进化范围内的生物体中。血清素通过与不同的细胞膜受体结合发挥其多样的作用，这些受体被分为许多组。血清素受体参与调节多种生理信号通路，属于G蛋白偶联受体（GPCRs）家族或配体门控离子通道家族。血清素能信号似乎在各种认知和行为功能（如睡眠、情绪、疼痛、焦虑、抑郁、攻击和学习）的产生和调节中起关键作用。血清素受体是许多疾病特别是神经精神疾病的药物靶点。血清素受体的信号传导机制和效率取决于它们快速进入多种构象状态的惊人能力。这种构象可塑性是血清素受体所显示的多种功能所必需的，它通过与各种配体结合来调节。在这篇综述中，我们简要概述了利用晶体学和冷冻电子显微镜生成和分析血清素受体高分辨率结构的最新进展。捕捉不同构象状态的结构对于理解这些受体的作用机制至关重要，这可为针对血清素受体的合理药物设计提供重要见解。我们还提供了关于膜脂（如胆固醇）与血清素受体相互作用研究的新信息和见解。我们设想，高分辨率结构分析和受体-脂质相互作用的明智结合将有助于全面理解GPCR的结构、功能和动力学，从而实现高效的药物发现。
