Similar voltage-sensor movement in spHCN channels can cause closing, opening, or inactivation.
Similar voltage-sensor movement in spHCN channels can cause closing, opening, or inactivation.
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DOI：
10.1085/jgp.202213170
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发表时间：
2023-05-01
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影响因子：
--
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我们在这里表明，突变超极化激活的环核苷酸门控（HCN）通道中类似的电压传感器运动可以导致更多的关闭或更多的开放取决于cAMP浓度，这表明电压传感器-门耦合很容易改变HCN通道。超极化激活的环核苷酸门控（HCN）通道有助于起搏神经元和心肌细胞的节律性放电。HCN通道的突变与心律失常和癫痫有关。HCN通道属于电压门控性K+通道超家族，大多数通过去极化激活。然而，HCN通道被超极化激活。HCN通道的这种反向门控极性背后的机制尚不清楚。我们在这里表明，海胆HCN（sphHCN）通道的C-末端部分的电压传感器的突变使用相同的电压传感器的运动，要么关闭或打开响应超极化取决于cAMP的存在或不存在。我们的研究结果支持在电压传感器的C-末端的非共价相互作用是HCN门控极性的关键。这些相互作用对于通道的正确关闭也是至关重要的，因为这些突变表现出大的组成性电流。由于类似的电压传感器运动可以在同一通道中引起去极化和超极化激活，这表明电压传感器和孔之间的耦合被改变以创建由不同极性打开的通道。我们还显示了一个相同的电压传感器的运动在激活和失活的sphHCN通道，并提出了一个模型sphHCN的激活和失活。我们的研究结果表明，通道打开相反的电压依赖性，如HCN和相关的EAG通道，使用相同的电压传感器的运动，但不同的耦合机制之间的电压传感器和门的可能性。
We show here that a similar voltage-sensor movement in mutant hyperpolarization-activated cyclic nucleotide-gated (HCN) channels can lead to more closing or more opening depending on the cAMP concentration, suggesting that voltage sensor-to-gate coupling is easily altered in HCN channels. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to the rhythmic firing of pacemaker neurons and cardiomyocytes. Mutations in HCN channels are associated with cardiac arrhythmia and epilepsy. HCN channels belong to the superfamily of voltage-gated K+ channels, most of which are activated by depolarization. HCN channels, however, are activated by hyperpolarization. The mechanism behind this reversed gating polarity of HCN channels is not clear. We here show that sea urchin HCN (spHCN) channels with mutations in the C-terminal part of the voltage sensor use the same voltage-sensor movement to either close or open in response to hyperpolarizations depending on the absence or presence of cAMP. Our results support that non-covalent interactions at the C-terminal end of the voltage sensor are critical for HCN gating polarity. These interactions are also critical for the proper closing of the channels because these mutations exhibit large constitutive currents. Since a similar voltage-sensor movement can cause both depolarization- and hyperpolarization-activation in the same channel, this suggests that the coupling between the voltage sensor and the pore is changed to create channels opened by different polarities. We also show an identical voltage-sensor movement in activated and inactivated spHCN channels and suggest a model for spHCN activation and inactivation. Our results suggest the possibility that channels open by opposite voltage dependence, such as HCN and the related EAG channels, use the same voltage-sensor movement but different coupling mechanisms between the voltage sensor and the gate.
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DOI：
10.1085/jgp.118.3.237
发表时间：
2001-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Wang J;Chen S;Siegelbaum SA
通讯作者：
Siegelbaum SA
DOI：
10.1074/jbc.m110.214650
发表时间：
2011-04-29
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Flynn GE;Zagotta WN
通讯作者：
Zagotta WN
影响因子：
64.5
作者：
Wang W;MacKinnon R
通讯作者：
MacKinnon R
影响因子：
64.8
作者：
Männikkö, R;Elinder, F;Larsson, HP
通讯作者：
Larsson, HP
影响因子：
5.3
作者：
Bruening-Wright, Andrew;Larsson, H. Peter
通讯作者：
Larsson, H. Peter