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The voltage sensor is responsible for {Delta}pH dependence in Hv1 channels [Biophysics and Computational Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-05-11 , DOI: 10.1073/pnas.2025556118
Emerson M. Carmona, Miguel Fernandez, Juan J. Alvear-Arias, Alan Neely, H. Peter Larsson, Osvaldo Alvarez, Jose Antonio Garate, Ramon Latorre, Carlos Gonzalez

The dissipation of acute acid loads by the voltage-gated proton channel (Hv1) relies on regulating the channel’s open probability by the voltage and the ΔpH across the membrane (ΔpH = pHex − pHin). Using monomeric Ciona-Hv1, we asked whether ΔpH-dependent gating is produced during the voltage sensor activation or permeation pathway opening. A leftward shift of the conductance-voltage (G-V) curve was produced at higher ΔpH values in the monomeric channel. Next, we measured the voltage sensor pH dependence in the absence of a functional permeation pathway by recording gating currents in the monomeric nonconducting D160N mutant. Increasing the ΔpH leftward shifted the gating charge-voltage (Q-V) curve, demonstrating that the ΔpH-dependent gating in Hv1 arises by modulating its voltage sensor. We fitted our data to a model that explicitly supposes the Hv1 voltage sensor free energy is a function of both the proton chemical and the electrical potential. The parameters obtained showed that around 60% of the free energy stored in the ΔpH is coupled to the Hv1 voltage sensor activation. Our results suggest that the molecular mechanism underlying the Hv1 ΔpH dependence is produced by protons, which alter the free-energy landscape around the voltage sensor domain. We propose that this alteration is produced by accessibility changes of the protons in the Hv1 voltage sensor during activation.



中文翻译:

电压传感器负责Hv1通道中的{Delta} pH依赖性[生物物理学和计算生物学]

电压门控质子通道(H v 1)消散的急性酸负荷依赖于通过电压和跨膜的ΔpH(ΔpH= pH ex -pH in)调节通道的打开概率。使用单体Ciona -H v如图1所示,我们询问在电压传感器激活或渗透路径打开期间是否产生了依赖于pH的门控。在单体通道中的较高pH值下,电导-电压(GV)曲线向左移动。接下来,我们通过记录单体非导电D160N突变体中的门控电流来测量在不存在功能性渗透途径的情况下电压传感器的pH依赖性。向左增加ΔpH会改变门控电荷电压(QV)曲线,表明H v 1中依赖于pH的门控是通过调制其电压传感器产生的。我们将数据拟合到明确假设H v的模型中1个电压传感器的自由能是质子化学物质和电势的函数。获得的参数表明,ΔpH中存储的大约60%的自由能与H v 1电压传感器的激活相关。我们的结果表明,H v 1ΔpH依赖性的分子机制是由质子产生的,质子改变了电压传感器域周围的自由能态。我们建议这种变化是由激活期间H v 1电压传感器中质子的可及性变化引起的。

更新日期:2021-05-03
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