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| Title | Resting state structure of the hyperdepolarization activated two-pore channel 3. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 117, Issue 4, Page 1988-1993, Year 2020 |
| Publish date | Jan 28, 2020 |
 Authors | Miles Sasha Dickinson / Alexander Myasnikov / Jacob Eriksen / Nicole Poweleit / Robert M Stroud /  |
| PubMed Abstract | 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 ...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 (V ∼ +75 mV), in contrast to other TPCs and Na 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. |
 External links | Proc Natl Acad Sci U S A / PubMed:31924746 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.11 Å |
| Structure data | EMDB-21015, PDB-6v1q: |
| Chemicals |  ChemComp-NA: |
| Source |
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 Keywords |  MEMBRANE PROTEIN / Voltag-gated ion channel / two-pore channel / TPC3 |
