CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits
CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits
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DOI：
10.7554/elife.01213
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发表时间：
2013-11-12
期刊：
影响因子：
7.7
通讯作者：
Dale, Nicholas
中科院分区：
文献类型：
--
作者：
Meigh, Louise;Greenhalgh, Sophie A.;Dale, Nicholas
CO2分压（PCO2）的稳态调节对生命至关重要。pH值的传感已被提出作为一个足够的代理PCO2和直接CO2传感很大程度上折扣的确定。在这里，我们表明，连接蛋白26（Cx26）半通道，因果关系与呼吸化疗敏感性，直接调制的二氧化碳。存在于CO2敏感性连接蛋白（Cx26、Cx30、Cx32）中但不存在于CO2不敏感性连接蛋白（Cx31）中的“氨甲酰化基序”包含Lys 125和另外四个氨基酸，所述氨基酸将Lys 125定向于连接蛋白六聚体的相邻亚基的Arg 104。将氨甲酰化基序引入Cx31产生了突变的半通道（mCx31），其通过PCO2的增加而打开。Cx26和mCx31中氨甲酰化基序的突变破坏了CO2敏感性。Cx26的过程粒度计算建模表明，Lys125和Arg104之间的氨基甲酸酯桥将半通道偏置为开放状态。Cx26的氨甲酰化为CO2的生理传感引入了新的转导原理。
Homeostatic regulation of the partial pressure of CO2 (PCO2) is vital for life. Sensing of pH has been proposed as a sufficient proxy for determination of PCO2 and direct CO2-sensing largely discounted. Here we show that connexin 26 (Cx26) hemichannels, causally linked to respiratory chemosensitivity, are directly modulated by CO2. A 'carbamylation motif', present in CO2-sensitive connexins (Cx26, Cx30, Cx32) but absent from a CO2-insensitive connexin (Cx31), comprises Lys125 and four further amino acids that orient Lys125 towards Arg104 of the adjacent subunit of the connexin hexamer. Introducing the carbamylation motif into Cx31 created a mutant hemichannel (mCx31) that was opened by increases in PCO2. Mutation of the carbamylation motif in Cx26 and mCx31 destroyed CO2 sensitivity. Course-grained computational modelling of Cx26 demonstrated that the proposed carbamate bridge between Lys125 and Arg104 biases the hemichannel to the open state. Carbamylation of Cx26 introduces a new transduction principle for physiological sensing of CO2.