Osmakov Dmitry I, Khasanov Timur A, Andreev Yaroslav A, Lyukmanova Ekaterina N, Kozlov Sergey A
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia.
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia.
Front Pharmacol. 2020 Jul 8;11:991. doi: 10.3389/fphar.2020.00991. eCollection 2020.
Acid-sensing ion channels (ASICs) are of the most sensitive molecular sensors of extracellular pH change in mammals. Six isoforms of these channels are widely represented in membranes of neuronal and non-neuronal cells, where these molecules are involved in different important regulatory functions, such as synaptic plasticity, learning, memory, and nociception, as well as in various pathological states. Structural and functional studies of both wild-type and mutant ASICs are essential for human care and medicine for the efficient treatment of socially significant diseases and ensure a comfortable standard of life. Ligands of ASICs serve as indispensable tools for these studies. Such bioactive compounds can be synthesized artificially. However, to date, the search for such molecules has been most effective amongst natural sources, such as animal venoms or plants and microbial extracts. In this review, we provide a detailed and comprehensive structural and functional description of natural compounds acting on ASICs, as well as the latest information on structural aspects of their interaction with the channels. Many of the examples provided in the review demonstrate the undoubted fundamental and practical successes of using natural toxins. Without toxins, it would not be possible to obtain data on the mechanisms of ASICs' functioning, provide detailed study of their pharmacological properties, or assess the contribution of the channels to development of different pathologies. The selectivity to different isoforms and variety in the channel modulation mode allow for the appraisal of prospective candidates for the development of new drugs.
酸敏感离子通道（ASICs）是哺乳动物细胞外pH变化最敏感的分子传感器之一。这些通道的六种亚型广泛存在于神经元和非神经元细胞膜中，在这些分子参与不同的重要调节功能，如突触可塑性、学习、记忆和痛觉感受，以及各种病理状态。野生型和突变型ASICs的结构和功能研究对于人类健康和医学有效治疗具有社会意义的疾病并确保舒适的生活标准至关重要。ASICs的配体是这些研究不可或缺的工具。这类生物活性化合物可以人工合成。然而，迄今为止，在动物毒液、植物和微生物提取物等天然来源中寻找此类分子最为有效。在这篇综述中，我们详细全面地描述了作用于ASICs的天然化合物的结构和功能，以及它们与通道相互作用的结构方面的最新信息。综述中提供的许多例子证明了使用天然毒素取得的毋庸置疑的基础和实际成功。没有毒素，就不可能获得关于ASICs功能机制的数据，无法对其药理学特性进行详细研究，也无法评估通道对不同病理发展的贡献。对不同亚型的选择性和通道调节模式的多样性有助于评估新药开发的潜在候选物。
