Novel Insights into the Structural Basis of pH-Sensitivity in Inward Rectifier K+ Channels Kir2.3
Novel Insights into the Structural Basis of pH-Sensitivity in Inward Rectifier K+ Channels Kir2.3
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DOI：
10.1159/000129629
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发表时间：
2008-04
影响因子：
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通讯作者：
O. Ureche;Ravshan Baltaev;L. Ureche;N. Strutz‐Seebohm;F. Lang;G. Seebohm
中科院分区：
文献类型：
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作者：
O. Ureche;Ravshan Baltaev;L. Ureche;N. Strutz‐Seebohm;F. Lang;G. Seebohm
Kir2 通道属于钾选择性通道家族，具有强内向整流特性。 Kir2.1、Kir2.2 和 Kir2.3 的异聚体组装在心室肌细胞、神经元和骨骼肌中形成膜电位稳定电流。 Kir2 通道对细胞外 pH 值的敏感性存在显着差异。细胞外组氨酸 Kir2.3(H117) 导致含有 Kir2.3 的 K 通道的 pH 依赖性。在这里，我们研究了残基 Kir2.3(H117) 与靠近选择性过滤器的保守半胱氨酸发生分子内相互作用的可能性。我们通过将半胱氨酸引入推定的氢键残基 (Kir2.3(H117C)) 中，设计了 Kir2.3 中的钴配位位点和还原/氧化敏感性，确认该残基与 Kir2.3(C141) 接近。使用 SCAM，我们确定了 Kir2.3(H117) 在外孔口中的位置，并将这些数据合并到 3D 模型中。我们得出的结论是，在低pH值下形成氢键可以稳定外孔域，有利于选择性过滤器处于稍微扭曲的构象，从而减少离子渗透。这些数据提供了对内向整流通道独特的 pH 调节的分子洞察。
The Kir2 channels belong to a family of potassium selective channels with characteristic strong inward rectification. Heteromeric assemblies of Kir2.1, Kir2.2 and Kir2.3 channels underly membrane potential stabilizing currents in ventricular myocytes, neurons and skeletal muscle. Kir2 channels differ substantially in their sensitivity to extracellular pH. The extracellular histidine Kir2.3(H117) contributes to the pH dependence of K-channels containing Kir2.3. Here, we study the possibility of intramolecular interactions of the residue Kir2.3(H117) with conserved cysteines in close proximity to the selectivity filter. We engineered a cobalt coordination site and reduction/oxidation sensitivity in Kir2.3 by introduction of a cysteine into the putatively hydrogen bonding residue (Kir2.3(H117C)) confirming that this residue is in proximity to Kir2.3(C141). Using SCAM we determined the location of the Kir2.3(H117) in the outer pore mouth and incorporated these data into a 3D model. We conclude that formation of a hydrogen bond at low pH may stabilize the outer pore domain to favour the selectivity filter in a slightly distorted conformation thus reducing ion permeation. The data provide molecular insight into the unique pH regulation of inward rectifier channels.