Histidine Residues Are Responsible for Bidirectional Effects of Zinc on Acid-Sensing Ion Channel 1a/3 Heteromeric Channels.
Histidine Residues Are Responsible for Bidirectional Effects of Zinc on Acid-Sensing Ion Channel 1a/3 Heteromeric Channels.
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DOI：
10.3390/biom10091264
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发表时间：
2020-09-02
期刊：
影响因子：
5.5
通讯作者：
Chu XP
中科院分区：
文献类型：
--
作者：
Jiang Q;Peterson AM;Chu Y;Yao X;Zha XM;Chu XP
酸敏感离子通道（ASIC）亚基1a和3分别在中枢和外周感觉神经元中高度表达。内源性生物分子锌在生理和病理生理条件下起着关键作用。在这里，我们发现，电流记录从异源表达ASIC 1a/3通道使用全细胞膜片钳技术调节锌具有双重作用。锌的共同应用剂量依赖性地增强了异聚体ASIC 1a/3电流的峰值幅度和持续分量;用3至100 µM的锌预处理产生了与共同应用相同的增强作用。然而，当锌浓度超过250 µM时，锌预处理诱导异聚体ASIC 1a/3通道的显著抑制。锌对异聚体ASIC 1a/3通道的增强作用是pH依赖性的，因为锌将ASIC 1a/3电流的pH依赖性从6.54的pH 50转移到6.77;而锌对ASIC 1a/3电流的抑制也是pH依赖性的。此外，我们系统地突变了ASIC 1a或ASIC 3胞外结构域中的组氨酸残基，发现ASIC 1a和ASIC 3中的组氨酸残基72和73以及ASIC 3中的组氨酸残基83负责锌对异聚体ASIC 1a/3通道的双向作用。这些发现表明，组氨酸残基的异源ASIC 1a/3通道的细胞外结构域是锌介导的作用的关键。
Acid-sensing ion channel (ASIC) subunits 1a and 3 are highly expressed in central and peripheral sensory neurons, respectively. Endogenous biomolecule zinc plays a critical role in physiological and pathophysiological conditions. Here, we found that currents recorded from heterologously expressed ASIC1a/3 channels using the whole-cell patch-clamp technique were regulated by zinc with dual effects. Co-application of zinc dose-dependently potentiated both peak amplitude and the sustained component of heteromeric ASIC1a/3 currents; pretreatment with zinc between 3 to 100 µM exerted the same potentiation as co-application. However, pretreatment with zinc induced a significant inhibition of heteromeric ASIC1a/3 channels when zinc concentrations were over 250 µM. The potentiation of heteromeric ASIC1a/3 channels by zinc was pH dependent, as zinc shifted the pH dependence of ASIC1a/3 currents from a pH50 of 6.54 to 6.77; whereas the inhibition of ASIC1a/3 currents by zinc was also pH dependent. Furthermore, we systematically mutated histidine residues in the extracellular domain of ASIC1a or ASIC3 and found that histidine residues 72 and 73 in both ASIC1a and ASIC3, and histidine residue 83 in the ASIC3 were responsible for bidirectional effects on heteromeric ASIC1a/3 channels by zinc. These findings suggest that histidine residues in the extracellular domain of heteromeric ASIC1a/3 channels are critical for zinc-mediated effects.
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酸性离子通道有助于神经毒性。
影响因子：
6.9
作者：
Chu XP;Grasing KA;Wang JQ
通讯作者：
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影响因子：
4.4
作者：
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作者：
Baron, A;Schaefer, L;Lazdunski, M
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Lazdunski, M
DOI：
10.1073/pnas.1407018111
发表时间：
2014-06-17
影响因子：
11.1
作者：
Du, Jianyang;Reznikov, Leah R.;Welsh, Michael J.
通讯作者：
Welsh, Michael J.