Regulation of neuronal connexin-36 channels by pH
Regulation of neuronal connexin-36 channels by pH
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DOI：
10.1073/pnas.0804189105
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发表时间：
2008-11-04
影响因子：
11.1
通讯作者：
Barrio, Luis C.
中科院分区：
文献类型：
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作者：
Gonzalez-Nieto, Daniel;Gomez-Hernandez, Juan M.;Barrio, Luis C.
通过电突触的神经传递在神经元之间的同步和神经元网络的振荡中起着重要的作用。事实上，电传输与癫痫的超同步电活动有关。我们研究了细胞内pH值对连接蛋白36（Cx 36）介导的电耦合强度的影响，Cx 36是脊椎动物电突触中的主要间隙连接蛋白。与其他连接蛋白亚型形成鲜明对比的是，当Cx 36在爪蟾卵母细胞和N2 A细胞中表达时，Cx 36通道的活性在脱水后而不是酸中毒后降低。碱化后Cx 36通道的解偶联发生在分析的脊椎动物直系同源物（人、小鼠、鸡、鲈鱼和旱冰鱼）中。虽然细胞内酸化引起了轻度或中度的增加，几乎所有这些通道的交界处的电导，耦合的滑冰Cx 35通道被部分阻断酸中毒。突变分析表明，Cx 36通道可能包含两个门控机制与相对的敏感性pH值。一个门，占主导地位的机制，关闭pathesis，它可能涉及的C-和IN-末端结构域之间的相互作用，而二级酸传感门只会导致轻微的，虽然饱和，酸中毒和pathesis后耦合的变化。因此，我们的结论是，神经元Cx 36通道进行独特的调节pH（i），因为它们的活动受到抑制，而不是酸中毒。这些数据提供了一个新的基础，以定义的相关性和后果的pH值依赖性的调制Cx 36突触在生理和病理条件下。
Neurotransmission through electrical synapses plays an important role in the spike synchrony among neurons and oscillation of neuronal networks. Indeed, electrical transmission has been implicated in the hypersynchronous electrical activity of epilepsy. We have investigated the influence of intracellular pH on the strength of electrical coupling mediated by connexin36 (Cx36), the principal gap junction protein in the electrical synapses of vertebrates. In striking contrast to other connexin isoforms, the activity of Cx36 channels decreases following alkalosis rather than acidosis when it is expressed in Xenopus oocytes and N2A cells. This uncoupling of Cx36 channels upon alkalinization occurred in the vertebrate orthologues analyzed (human, mouse, chicken, perch, and skate). While intracellular acidification caused a mild or moderate increase in the junctional conductance of virtually all these channels, the coupling of the skate Cx35 channel was partially blocked by acidosis. The mutational analysis suggests that the Cx36 channels may contain two gating mechanisms operating with opposing sensitivity to pH. One gate, the dominant mechanism, closes for alkalosis and it probably involves an interaction between the C- and IN-terminal domains, while a secondary acid sensing gate only causes minor, albeit saturating, changes in coupling following acidosis and alkalosis. Thus, we conclude that neuronal Cx36 channels undergo unique regulation by pH(i) since their activity is inhibited by alkalosis rather than acidosis. These data provide a novel basis to define the relevance and consequences of the pH-dependent modulation of Cx36 synapses under physiological and pathological conditions.