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Molecular dissection of multiphase inactivation of the bacterial sodium channel NaVAb.

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Gamal El-Din TM, Lenaeus MJ, Ramanadane K, Zheng N, Catterall WA
OpenAccess logo J Gen Physiol 151 174-185 (2019)
Related entries: 6mwb, 6mwd, 6mwg

Cited: 17 times
EuropePMC logo PMID: 30510035

Abstract

Homotetrameric bacterial voltage-gated sodium channels share major biophysical features with their more complex eukaryotic counterparts, including a slow-inactivation mechanism that reduces ion-conductance activity during prolonged depolarization through conformational changes in the pore. The bacterial sodium channel NaVAb activates at very negative membrane potentials and inactivates through a multiphase slow-inactivation mechanism. Early voltage-dependent inactivation during one depolarization is followed by late use-dependent inactivation during repetitive depolarization. Mutations that change the molecular volume of Thr206 in the pore-lining S6 segment can enhance or strongly block early voltage-dependent inactivation, suggesting that this residue serves as a molecular hub controlling the coupling of activation to inactivation. In contrast, truncation of the C-terminal tail enhances the early phase of inactivation yet completely blocks late use-dependent inactivation. Determination of the structure of a C-terminal tail truncation mutant and molecular modeling of conformational changes at Thr206 and the S6 activation gate led to a two-step model of these gating processes. First, bending of the S6 segment, local protein interactions dependent on the size of Thr206, and exchange of hydrogen-bonding partners at the level of Thr206 trigger pore opening followed by the early phase of voltage-dependent inactivation. Thereafter, conformational changes in the C-terminal tail lead to late use-dependent inactivation. These results have important implications for the sequence of conformational changes that lead to multiphase inactivation of NaVAb and other sodium channels.

Articles - 6mwa mentioned but not cited (3)

  1. 2StrucCompare: a webserver for visualizing small but noteworthy differences between protein tertiary structures through interrogation of the secondary structure content. Drew ED, Janes RW. Nucleic Acids Res 47 W477-W481 (2019)
  2. Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice. Echevarria-Cooper DM, Hawkins NA, Misra SN, Huffman AM, Thaxton T, Thompson CH, Ben-Shalom R, Nelson AD, Lipkin AM, George AL, Bender KJ, Kearney JA. Hum Mol Genet 31 2964-2988 (2022)
  3. Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel NaV1.7. Wisedchaisri G, Gamal El-Din TM, Zheng N, Catterall WA. Proc Natl Acad Sci U S A 120 e2219624120 (2023)


Reviews citing this publication (6)

  1. Sodium channelopathies of skeletal muscle and brain. Mantegazza M, Cestèle S, Catterall WA. Physiol Rev 101 1633-1689 (2021)
  2. The conformational cycle of a prototypical voltage-gated sodium channel. Catterall WA, Wisedchaisri G, Zheng N. Nat Chem Biol 16 1314-1320 (2020)
  3. Druggability of Voltage-Gated Sodium Channels-Exploring Old and New Drug Receptor Sites. Wisedchaisri G, Gamal El-Din TM. Front Pharmacol 13 858348 (2022)
  4. Fenestropathy of Voltage-Gated Sodium Channels. Gamal El-Din TM, Lenaeus MJ. Front Pharmacol 13 842645 (2022)
  5. Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology. Catterall WA. Channels (Austin) 17 2281714 (2023)
  6. When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of Nav1.5. Gamal El-Din TM. Cells 11 3714 (2022)

Articles citing this publication (8)



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