Evlanenkov Konstantin K, Komarova Margarita S, Dron Mikhail Y, Nikolaev Maxim V, Zhukovskaya Olga N, Gurova Nataliya A, Tikhonov Denis B
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia.
Research Institute of Physical and Organic Chemistry, Southern Federal University, Rostov-on-Don, Russia.
Front Physiol. 2023 Jan 12;14:1018551. doi: 10.3389/fphys.2023.1018551. eCollection 2023.
The pharmacology of acid-sensitive ion channels (ASICs) is diverse, but potent and selective modulators, for instance for ASIC2a, are still lacking. In the present work we studied the effect of five 2-aminobenzimidazole derivatives on native ASICs in rat brain neurons and recombinant receptors expressed in CHO cells using the whole-cell patch clamp method. 2-aminobenzimidazole selectively potentiated ASIC3. Compound Ru-1355 strongly enhanced responses of ASIC2a and caused moderate potentiation of native ASICs and heteromeric ASIC1a/ASIC2a. The most active compound, Ru-1199, caused the strongest potentiation of ASIC2a, but also potentiated native ASICs, ASIC1a and ASIC3. The potentiating effects depended on the pH and was most pronounced with intermediate acidifications. In the presence of high concentrations of Ru-1355 and Ru-1199, the ASIC2a responses were biphasic, the initial transient currents were followed by slow component. These slow additional currents were weakly sensitive to the acid-sensitive ion channels pore blocker diminazene. We also found that sustained currents mediated by ASIC2a and ASIC3 are less sensitive to diminazene than the peak currents. Different sensitivities of peak and sustained components to the pore-blocking drug suggest that they are mediated by different open states. We propose that the main mechanism of action of 2-aminobenzimidazole derivatives is potentiation of the open state with slow kinetics of activation and desensitization.
酸敏感离子通道（ASICs）的药理学特性多样，但目前仍缺乏针对ASIC2a等的强效且选择性的调节剂。在本研究中，我们采用全细胞膜片钳技术，研究了5种2-氨基苯并咪唑衍生物对大鼠脑神经元中天然ASICs以及CHO细胞中表达的重组受体的作用。2-氨基苯并咪唑选择性增强ASIC3。化合物Ru-1355强烈增强ASIC2a的反应，并对天然ASICs和异聚体ASIC1a/ASIC2a产生中度增强作用。活性最强的化合物Ru-1199对ASIC2a的增强作用最强，但也增强了天然ASICs、ASIC1a和ASIC3。增强作用依赖于pH值，在中等酸化程度时最为明显。在高浓度的Ru-1355和Ru-1199存在下，ASIC2a的反应呈双相性，初始瞬态电流之后是缓慢成分。这些缓慢的额外电流对酸敏感离子通道孔道阻断剂地美硝唑的敏感性较弱。我们还发现，由ASIC2a和ASIC3介导的持续电流对地美硝唑的敏感性低于峰值电流。峰值成分和持续成分对孔道阻断药物的不同敏感性表明它们由不同的开放状态介导。我们提出，2-氨基苯并咪唑衍生物的主要作用机制是增强具有缓慢激活和脱敏动力学的开放状态。
