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Updated: Sep 22, 2025

Reconstitution of a Transmembrane Protein, the Voltage-gated Ion Channel, KvAP, into Giant Unilamellar Vesicles for Microscopy and Patch Clamp Studies
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Reconstitution of a Transmembrane Protein, the Voltage-gated Ion Channel, KvAP, into Giant Unilamellar Vesicles for Microscopy and Patch Clamp Studies

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Activation and closed-state inactivation mechanisms of the human voltage-gated KV4 channel complexes

Wenlei Ye1, Hongtu Zhao2, Yaxin Dai2

  • 1Department of Physiology, University of California, San Francisco, CA 94158, USA.

Molecular Cell
|May 21, 2022
PubMed

Insights

Voltage-gated ion channel inactivation, crucial for membrane excitability, can occur in closed or open states. This study reveals the novel molecular mechanism of closed-state inactivation in KV4 channels using cryo-EM structures.

Area of Science:

  • Molecular and Cellular Biology
  • Neuroscience
  • Biophysics

Background:

  • Voltage-gated ion channel activity relies on activation and inactivation processes.
  • Inactivation limits ion conduction and is vital for membrane excitability.
  • While open-state inactivation is understood, the molecular basis of closed-state inactivation remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying closed-state inactivation in KV4 channels.
  • To determine the structural basis of KV4 channel gating and modulation by auxiliary subunits.
  • To provide insights into voltage-dependent activation.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine high-resolution structures.
  • Structural analysis of human KV4.2 channel complexes in various functional states (inactivated, open, closed, resting).
  • Investigation of channel modulation by KChIP2 and DPP6 auxiliary subunits.

Main Results:

  • Reported cryo-EM structures of human KV4.2 channels in inactivated, open, and closed states.
  • Identified a novel mechanism for closed-state inactivation involving symmetry breakdown and partial pore closure by S4-S5 linkers.
  • Captured a putative resting state, illustrating voltage sensor control of the pore.
  • Provided structural insights into KV4 channel modulation by KChIP2 and DPP6.

Conclusions:

  • Elucidated the distinct molecular mechanisms of closed-state inactivation in KV4 channels.
  • Advanced understanding of voltage-dependent activation and pore gating.
  • Offered structural basis for auxiliary subunit modulation of KV4 channels.
Keywords:
channel gatingclosed-state inactivationcryo-EMopen-state inactivationpotassium channelsodium channelsymmetry breakdownvoltage-gated ion channel

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