Osmakov Dmitry I, Koshelev Sergey G, Andreev Yaroslav A, Kozlov Sergey A
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesMoscow, Russia.
Institute of Molecular Medicine, Sechenov First Moscow State Medical UniversityMoscow, Russia.
Front Mol Neurosci. 2017 Sep 13;10:282. doi: 10.3389/fnmol.2017.00282. eCollection 2017.
Acid-sensing ion channels (ASICs) ASIC3 expressed mainly in peripheral sensory neurons play an important role in pain perception and inflammation development. In response to acidic stimuli, they can generate a unique biphasic current. At physiological pH 7.4, human ASIC3 isoform (hASIC3) is desensitized and able to generate only a sustained current. We found endogenous isoquinoline alkaloids (EIAs), which restore hASIC3 from desensitization and recover the transient component of the current. Similarly, rat ASIC3 isoform (rASIC3) can also be restored from desensitization (at pH < 7.0) by EIAs with the same potency. At physiological pH and above, EIAs at high concentrations were able to effectively activate hASIC3 and rASIC3. Thus, we found first endogenous agonists of ASIC3 channels that could both activate and prevent or reverse desensitization of the channel. The decrease of EIA levels could be suggested as a novel therapeutic strategy for treatment of pain and inflammation.
酸敏感离子通道（ASICs）中的ASIC3主要在外周感觉神经元中表达，在疼痛感知和炎症发展中起重要作用。响应酸性刺激时，它们可产生独特的双相电流。在生理pH值7.4时，人ASIC3亚型（hASIC3）脱敏，仅能产生持续电流。我们发现内源性异喹啉生物碱（EIAs）可使hASIC3从脱敏状态恢复，并恢复电流的瞬态成分。同样，大鼠ASIC3亚型（rASIC3）在pH < 7.0时也能被具有相同效力的EIAs从脱敏状态恢复。在生理pH值及以上，高浓度的EIAs能够有效激活hASIC3和rASIC3。因此，我们首次发现了ASIC3通道的内源性激动剂，其既能激活通道，又能防止或逆转通道的脱敏。EIA水平的降低可作为治疗疼痛和炎症的一种新的治疗策略。
