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Voltage-Dependent Potassium Current Recording on H9c2 Cardiomyocytes via the Whole-Cell Patch-Clamp Technique
Published on: November 11, 2022
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Isoleucine gate blocks K+ conduction in C-type inactivation
Werner Treptow1,2, Yichen Liu3, Carlos A Z Bassetto2
1Laboratório de Biologia Teórica e Computacional (LBTC), Universidade de Brasília, Brasilia, Brazil.
Elife
|November 12, 2024
Summary
C-type inactivation in voltage-gated potassium (Kv) channels involves a hydrophobic gate at I398, not just the dilated selectivity filter. This gate is crucial for blocking ion conduction and a target for drug development.
Area of Science:
- Molecular and Cellular Biology
- Biophysics
- Structural Biology
Background:
- Voltage-gated potassium (Kv) channels regulate cellular excitability.
- C-type inactivation is a key mechanism controlling Kv channel function.
- Previous structural studies proposed a dilated selectivity filter as the non-conductive state.
Purpose of the Study:
- To investigate the structural basis of C-type inactivation in Kv channels.
- To reconcile structural findings with functional data on Kv channel inactivation.
- To identify key molecular determinants of ion conduction block.
Main Methods:
- Molecular dynamics simulations of Kv channel mutants.
- Electrophysiological recordings to measure ionic currents.
- Structural analysis of channel conformations.
Main Results:
- The dilated selectivity filter in kv1.2-kv2.1-3m is conductive, not fully non-conductive.
- A hydrophobic gate formed by isoleucine 398 (I398) residues is essential for blocking ion conduction.
- Mutating I398 to asparagine restores ion permeation but retains C-type inactivation.
- This I398 gate is a target for quaternary ammonium blockers.
Conclusions:
- C-type inactivation requires a conformational change involving the I398 hydrophobic gate, located below the selectivity filter.
- The I398 gate is a critical component of the Kv channel inactivation machinery.
- This finding opens avenues for developing drugs targeting Kv channel gating states.
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