Resting state structure of the hyperdepolarization activated two-pore channel 3
Voltage-gated ion channels endow membranes with excitability and the means to propagate action potentials that form the basis of all neuronal signaling. We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is dist...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2020-01, Vol.117 (4), p.1988-1993 |
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| container_end_page | 1993 |
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| container_issue | 4 |
| container_start_page | 1988 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 117 |
| creator | Dickinson, Miles Sasha Myasnikov, Alexander Eriksen, Jacob Poweleit, Nicole Stroud, Robert M. |
| description | Voltage-gated ion channels endow membranes with excitability and the means to propagate action potentials that form the basis of all neuronal signaling. We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V50 ∼ +75 mV), in contrast to other TPCs and NaV channels that activate between −20 and 0 mV. We present electrophysiological evidence that TPC3 voltage activation depends only on voltage sensing domain 2 (VSD2) and that each of the three gating arginines in VSD2 reduces the activation threshold. The structure presents a chemical basis for sodium selectivity, and a constricted gate suggests a closed pore consistent with extreme voltage dependence. The structure, confirmed by our electrophysiology, illustrates the configuration of a bona fide resting state voltage sensor, observed without the need for any inhibitory ligand, and independent of any chemical or mutagenic alteration. |
| doi_str_mv | 10.1073/pnas.1915144117 |
| format | Article |
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We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V50 ∼ +75 mV), in contrast to other TPCs and NaV channels that activate between −20 and 0 mV. We present electrophysiological evidence that TPC3 voltage activation depends only on voltage sensing domain 2 (VSD2) and that each of the three gating arginines in VSD2 reduces the activation threshold. The structure presents a chemical basis for sodium selectivity, and a constricted gate suggests a closed pore consistent with extreme voltage dependence. 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We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V50 ∼ +75 mV), in contrast to other TPCs and NaV channels that activate between −20 and 0 mV. We present electrophysiological evidence that TPC3 voltage activation depends only on voltage sensing domain 2 (VSD2) and that each of the three gating arginines in VSD2 reduces the activation threshold. The structure presents a chemical basis for sodium selectivity, and a constricted gate suggests a closed pore consistent with extreme voltage dependence. 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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2020-01, Vol.117 (4), p.1988-1993 |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Action Potentials Activation Biological Sciences Channel gating Cryoelectron Microscopy Depolarization Electrophysiology Excitability HEK293 Cells Humans Ion Channel Gating - physiology Ion channels Ions Membrane potential Membranes Models, Molecular Organic chemistry Potassium Protein Conformation Selectivity Sodium Sodium - metabolism Sodium channels (voltage-gated) |
| title | Resting state structure of the hyperdepolarization activated two-pore channel 3 |
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