Molecular Mechanism of Depolarization-Dependent Inactivation in W366F Mutant of Kv1.2

Hiroko X. Kondo, Norio Yoshida, Matsuyuki Shirota, Kengo Kinoshita

Research output: Contribution to journalArticle

Abstract

Voltage-gated potassium channels play crucial roles in regulating membrane potential. They are activated by membrane depolarization, allowing the selective permeation of K + ions across the plasma membrane, and enter a nonconducting state after lasting depolarization, a process known as inactivation. Inactivation in voltage-activated potassium channels occurs through two distinct mechanisms, N-type and C-type inactivation. C-type inactivation is caused by conformational changes in the extracellular mouth of the channel, whereas N-type inactivation is elicited by changes in the cytoplasmic mouth of the protein. The W434F-mutated Shaker channel is known as a nonconducting mutant and is in a C-type inactivation state at a depolarizing membrane potential. To clarify the structural properties of C-type inactivated protein, we performed molecular dynamics simulations of the wild-type and W366F (corresponding to W434F in Shaker) mutant of the Kv1.2-2.1 chimera channel. The W366F mutant was in a nearly nonconducting state with a depolarizing voltage and recovered from inactivation with a reverse voltage. Our simulations and three-dimensional reference interaction site model analysis suggested that structural changes in the selectivity filter upon membrane depolarization trap K + ions around the inner mouth of the selectivity filter and prevent ion permeation. This pore restriction is involved in the molecular mechanism of C-type inactivation.

Original languageEnglish
Pages (from-to)10825-10833
Number of pages9
JournalJournal of Physical Chemistry B
Volume122
Issue number48
DOIs
Publication statusPublished - Dec 6 2018

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Depolarization
depolarization
deactivation
Mouth
Ions
Membranes
Membrane Potentials
Electric potential
Permeation
Potassium
Voltage-Gated Potassium Channels
mouth
membranes
Potassium Channels
Molecular Dynamics Simulation
Protein C
Proteins
electric potential
Cell membranes
Cell Membrane

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Molecular Mechanism of Depolarization-Dependent Inactivation in W366F Mutant of Kv1.2. / Kondo, Hiroko X.; Yoshida, Norio; Shirota, Matsuyuki; Kinoshita, Kengo.

In: Journal of Physical Chemistry B, Vol. 122, No. 48, 06.12.2018, p. 10825-10833.

Research output: Contribution to journalArticle

Kondo, Hiroko X. ; Yoshida, Norio ; Shirota, Matsuyuki ; Kinoshita, Kengo. / Molecular Mechanism of Depolarization-Dependent Inactivation in W366F Mutant of Kv1.2. In: Journal of Physical Chemistry B. 2018 ; Vol. 122, No. 48. pp. 10825-10833.
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