A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels
ASICs are proton-gated sodium channels expressed in neurons. Structures of chicken ASIC1 in three conformations have advanced understanding of proton-mediated gating; however, a molecular mechanism describing desensitization from open and pre-open states (steady-state desensitization or SSD) remains...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/45851 |
| _version_ | 1811253127514423296 |
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| author | Yangyu Wu Zhuyuan Chen Cecilia M Canessa |
| author_facet | Yangyu Wu Zhuyuan Chen Cecilia M Canessa |
| author_sort | Yangyu Wu |
| collection | DOAJ |
| description | ASICs are proton-gated sodium channels expressed in neurons. Structures of chicken ASIC1 in three conformations have advanced understanding of proton-mediated gating; however, a molecular mechanism describing desensitization from open and pre-open states (steady-state desensitization or SSD) remains elusive. A distinct feature of the desensitized state is an 180o rotation of residues L415 and N416 in the β11- β12 linker that was proposed to mediate desensitization; whether and how it translates into desensitization has not been explored yet. Using electrophysiological measurements of injected Xenopus oocytes, we show that Q276 in β9 strand works with L415 and N416 to mediate both types of desensitization in ASIC1a, ASIC2a and ASIC3. Q276 functions as a valve that enables or restricts rotation of L415 and N416 to keep the linker compressed, its relaxation lengthens openings and leads to sustained currents. At low proton concentrations, the proposed mechanism working in only one of three subunits of the channel is sufficient to induce SSD. |
| first_indexed | 2024-04-12T16:45:08Z |
| format | Article |
| id | doaj.art-45151b0abd764d61baee06f2cd535376 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:45:08Z |
| publishDate | 2019-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-45151b0abd764d61baee06f2cd5353762022-12-22T03:24:36ZengeLife Sciences Publications LtdeLife2050-084X2019-05-01810.7554/eLife.45851A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channelsYangyu Wu0Zhuyuan Chen1Cecilia M Canessa2https://orcid.org/0000-0003-0536-2679Department of Basic Sciences, Tsinghua University School of Medicine, Beijing, ChinaDepartment of Basic Sciences, Tsinghua University School of Medicine, Beijing, ChinaDepartment of Basic Sciences, Tsinghua University School of Medicine, Beijing, ChinaASICs are proton-gated sodium channels expressed in neurons. Structures of chicken ASIC1 in three conformations have advanced understanding of proton-mediated gating; however, a molecular mechanism describing desensitization from open and pre-open states (steady-state desensitization or SSD) remains elusive. A distinct feature of the desensitized state is an 180o rotation of residues L415 and N416 in the β11- β12 linker that was proposed to mediate desensitization; whether and how it translates into desensitization has not been explored yet. Using electrophysiological measurements of injected Xenopus oocytes, we show that Q276 in β9 strand works with L415 and N416 to mediate both types of desensitization in ASIC1a, ASIC2a and ASIC3. Q276 functions as a valve that enables or restricts rotation of L415 and N416 to keep the linker compressed, its relaxation lengthens openings and leads to sustained currents. At low proton concentrations, the proposed mechanism working in only one of three subunits of the channel is sufficient to induce SSD.https://elifesciences.org/articles/45851ASICdesensitizationb11-b12 linkerQ-valve mechanismelectrophysiology |
| spellingShingle | Yangyu Wu Zhuyuan Chen Cecilia M Canessa A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels eLife ASIC desensitization b11-b12 linker Q-valve mechanism electrophysiology |
| title | A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels |
| title_full | A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels |
| title_fullStr | A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels |
| title_full_unstemmed | A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels |
| title_short | A valve-like mechanism controls desensitization of functional mammalian isoforms of acid-sensing ion channels |
| title_sort | valve like mechanism controls desensitization of functional mammalian isoforms of acid sensing ion channels |
| topic | ASIC desensitization b11-b12 linker Q-valve mechanism electrophysiology |
| url | https://elifesciences.org/articles/45851 |
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