ASIC1a亚基之间的氧化还原调节的亚基间二硫键形成。
Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits.
作者信息
Zha Xiang-ming, Wang Runping, Collier Dan M, Snyder Peter M, Wemmie John A, Welsh Michael J
机构信息
Howard Hughes Medical Institute and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
出版信息
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3573-8. doi: 10.1073/pnas.0813402106. Epub 2009 Feb 13.
The acid-sensing ion channel-1a (ASIC1a) is composed of 3 subunits and is activated by a decrease in extracellular pH. It plays an important role in diseases associated with a reduced pH and production of oxidants. Previous work showed that oxidants reduce ASIC1a currents. However, the effects on channel structure and composition are unknown. We found that ASIC1a formed inter-subunit disulfide bonds and the oxidant H(2)O(2) increased this link between subunits. Cys-495 in the ASIC1a C terminus was particularly important for inter-subunit disulfide bond formation, although other C-terminal cysteines contributed. Inter-subunit disulfide bonds also produced some ASIC1a complexes larger than trimers. Inter-subunit disulfide bond formation reduced the proportion of ASIC1a located on the cell surface and contributed to the H(2)O(2)-induced decrease in H(+)-gated current. These results indicate that channel function is controlled by disulfide bond formation between intracellular residues on distinct ASIC1a subunits. They also suggest a mechanism by which the redox state can dynamically regulate membrane protein activity by forming intracellular bridges.
酸敏感离子通道1a（ASIC1a）由3个亚基组成，可被细胞外pH值降低激活。它在与pH值降低和氧化剂产生相关的疾病中起重要作用。先前的研究表明，氧化剂会降低ASIC1a电流。然而，其对通道结构和组成的影响尚不清楚。我们发现ASIC1a形成了亚基间二硫键，氧化剂过氧化氢（H₂O₂）增加了亚基之间的这种连接。ASIC1a C末端的半胱氨酸495（Cys-495）对亚基间二硫键的形成尤为重要，尽管其他C末端半胱氨酸也有作用。亚基间二硫键还产生了一些大于三聚体的ASIC1a复合物。亚基间二硫键的形成降低了位于细胞表面的ASIC1a的比例，并导致了H₂O₂诱导的H⁺门控电流的降低。这些结果表明，通道功能受不同ASIC1a亚基细胞内残基之间二硫键形成的控制。它们还提示了一种氧化还原状态可通过形成细胞内桥来动态调节膜蛋白活性的机制。
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