Sea anemone Cys-ladder peptide Ms13-1 induces a pain response as a positive modulator of acid-sensing ion channel 1a.

Timur A Khasanov, Konstantin S Mineev, Aleksandr P Kalinovskii, Yuliya V Korolkova, Victor A Palikov, Yulia A Palikova, Igor A Dyachenko, Sergey A Kozlov, Yaroslav A Andreev, Dmitry I Osmakov
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Abstract

Acid-sensing ion channel 1a (ASIC1a) is involved in processes associated with fear, learning, and neurodegeneration within the central nervous system. However, ASIC1a is also abundant in the peripheral nervous system, where its role is still poorly understood, largely due to the lack of selective ligands. In this study, we present the discovery of the first selective positive allosteric modulator for ASIC1a, isolated from the sea anemone Metridium senile. The active compound, a peptide named Ms13-1, features a novel type of fold named 'Cys-ladder'. Ms13-1 exhibits high affinity and selectivity for ASIC1a, enhancing channel activation in response to a broad range of acidic stimuli (pH 6.9-5.5) without altering the proton affinity for the channel. Moreover, injection of Ms13-1 into the hind paw of mice provokes robust and long-lasting pain-related behavior, which is significantly attenuated by a selective ASIC1 antagonist. The discovery of this novel selective positive allosteric modulator opens up new perspectives to investigate the role of ASIC1a in various physiological processes.

海葵Cys-ladder肽Ms13-1作为酸感离子通道1a的正向调节剂诱导疼痛反应。
酸感离子通道1a (ASIC1a)参与中枢神经系统中与恐惧、学习和神经变性相关的过程。然而,ASIC1a在周围神经系统中也大量存在,其作用仍然知之甚少,这主要是由于缺乏选择性配体。在这项研究中,我们首次从海葵中分离出ASIC1a的选择性正变构调节剂。活性化合物是一种名为Ms13-1的肽,具有一种名为“Cys-ladder”的新型折叠。Ms13-1对ASIC1a具有高亲和力和选择性,在不改变通道的质子亲和力的情况下,增强了通道对广泛酸性刺激(pH 6.9-5.5)的激活。此外,将Ms13-1注射到小鼠的后爪中,会引发强烈而持久的疼痛相关行为,而选择性ASIC1拮抗剂会显著减弱这种行为。这种新型选择性正变构调节剂的发现为研究ASIC1a在各种生理过程中的作用开辟了新的视角。
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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