A new polymodal gating model of the proton-activated chloride channel.
The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing modera...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-09-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002309&type=printable |
| _version_ | 1797670257003855872 |
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| author | Piao Zhao Cheng Tang Yuqin Yang Zhen Xiao Samantha Perez-Miller Heng Zhang Guoqing Luo Hao Liu Yaqi Li Qingyi Liao Fan Yang Hao Dong Rajesh Khanna Zhonghua Liu |
| author_facet | Piao Zhao Cheng Tang Yuqin Yang Zhen Xiao Samantha Perez-Miller Heng Zhang Guoqing Luo Hao Liu Yaqi Li Qingyi Liao Fan Yang Hao Dong Rajesh Khanna Zhonghua Liu |
| author_sort | Piao Zhao |
| collection | DOAJ |
| description | The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing moderate activation by acting on its proton gating. However, at higher concentrations, C77304 acted as a weak inhibitor, suppressing channel activity. This dual function was achieved by interacting with 2 modulatory sites of the channel, each with different affinities and dependencies on the channel's state. Moreover, we discovered a protonation-independent voltage activation of the PAC channel that appears to operate through an ion-flux gating mechanism. Through scanning-mutagenesis and molecular dynamics simulation, we confirmed that E181, E257, and E261 in the human PAC channel serve as primary proton sensors, as their alanine mutations eliminated the channel's proton gating while sparing the voltage-dependent gating. This proton-sensing mechanism was conserved among orthologous PAC channels from different species. Collectively, our data unveils the polymodal gating and proton-sensing mechanisms in the PAC channel that may inspire potential drug development. |
| first_indexed | 2024-03-11T20:57:05Z |
| format | Article |
| id | doaj.art-ba3078cd09e54fe1adc6f2c08397fc90 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-03-11T20:57:05Z |
| publishDate | 2023-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-ba3078cd09e54fe1adc6f2c08397fc902023-09-30T05:30:38ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-09-01219e300230910.1371/journal.pbio.3002309A new polymodal gating model of the proton-activated chloride channel.Piao ZhaoCheng TangYuqin YangZhen XiaoSamantha Perez-MillerHeng ZhangGuoqing LuoHao LiuYaqi LiQingyi LiaoFan YangHao DongRajesh KhannaZhonghua LiuThe proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing moderate activation by acting on its proton gating. However, at higher concentrations, C77304 acted as a weak inhibitor, suppressing channel activity. This dual function was achieved by interacting with 2 modulatory sites of the channel, each with different affinities and dependencies on the channel's state. Moreover, we discovered a protonation-independent voltage activation of the PAC channel that appears to operate through an ion-flux gating mechanism. Through scanning-mutagenesis and molecular dynamics simulation, we confirmed that E181, E257, and E261 in the human PAC channel serve as primary proton sensors, as their alanine mutations eliminated the channel's proton gating while sparing the voltage-dependent gating. This proton-sensing mechanism was conserved among orthologous PAC channels from different species. Collectively, our data unveils the polymodal gating and proton-sensing mechanisms in the PAC channel that may inspire potential drug development.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002309&type=printable |
| spellingShingle | Piao Zhao Cheng Tang Yuqin Yang Zhen Xiao Samantha Perez-Miller Heng Zhang Guoqing Luo Hao Liu Yaqi Li Qingyi Liao Fan Yang Hao Dong Rajesh Khanna Zhonghua Liu A new polymodal gating model of the proton-activated chloride channel. PLoS Biology |
| title | A new polymodal gating model of the proton-activated chloride channel. |
| title_full | A new polymodal gating model of the proton-activated chloride channel. |
| title_fullStr | A new polymodal gating model of the proton-activated chloride channel. |
| title_full_unstemmed | A new polymodal gating model of the proton-activated chloride channel. |
| title_short | A new polymodal gating model of the proton-activated chloride channel. |
| title_sort | new polymodal gating model of the proton activated chloride channel |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002309&type=printable |
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