CNRS (Centre National de la Recherche Scientifique), IPMC (Institut de Pharmacologie Moléculaire et Cellulaire), LabEx ICST (Laboratory of Excellence in Ion Channel Science and Therapeutics), FHU InovPain (Fédération Hospitalo-Universitaire "Innovative Solutions in Refractory Chronic Pain"), Université Côte d'Azur, 660 Route des Lucioles, Sophia-Antipolis, 06560 Nice, France.
Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Toxins (Basel). 2022 Oct 17;14(10):709. doi: 10.3390/toxins14100709.
Acid-sensing ion channels (ASICs) are voltage-independent H-gated cation channels largely expressed in the nervous system of rodents and humans. At least six isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) associate into homotrimers or heterotrimers to form functional channels with highly pH-dependent gating properties. This review provides an update on the pharmacological profiles of animal peptide toxins targeting ASICs, including PcTx1 from tarantula and related spider toxins, APETx2 and APETx-like peptides from sea anemone, and mambalgin from snake, as well as the dimeric protein snake toxin MitTx that have all been instrumental to understanding the structure and the pH-dependent gating of rodent and human cloned ASICs and to study the physiological and pathological roles of native ASICs in vitro and in vivo. ASICs are expressed all along the pain pathways and the pharmacological data clearly support a role for these channels in pain. ASIC-targeting peptide toxins interfere with ASIC gating by complex and pH-dependent mechanisms sometimes leading to opposite effects. However, these dual pH-dependent effects of ASIC-inhibiting toxins (PcTx1, mambalgin and APETx2) are fully compatible with, and even support, their analgesic effects in vivo, both in the central and the peripheral nervous system, as well as potential effects in humans.
酸敏离子通道（ASICs）是电压不依赖性的 H 门控阳离子通道，主要在啮齿动物和人类的神经系统中表达。至少有六种亚型（ASIC1a、1b、2a、2b、3 和 4）形成同源三聚体或异源三聚体，形成具有高度 pH 依赖性门控特性的功能性通道。本文综述了针对 ASICs 的动物肽毒素的药理学特性，包括来自狼蛛和相关蜘蛛毒素的 PcTx1、来自海葵的 APETx2 和 APETx 样肽，以及来自蛇的 mambalgin，以及二聚体蛋白蛇毒素 MitTx，这些毒素对于理解啮齿动物和人类克隆 ASIC 的结构和 pH 依赖性门控以及研究内源性 ASIC 在体外和体内的生理和病理作用都非常重要。ASICs 沿疼痛途径表达，药理学数据清楚地表明这些通道在疼痛中起作用。靶向 ASIC 的肽毒素通过复杂且依赖 pH 的机制干扰 ASIC 的门控，有时会导致相反的效果。然而，这些 ASIC 抑制毒素（PcTx1、mambalgin 和 APETx2）的双重 pH 依赖性效应与它们在体内的镇痛作用完全一致，无论是在中枢神经系统还是外周神经系统，以及它们在人类中的潜在作用。
