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Molecular driving forces determining potassium channel slow inactivation.
Julio F Cordero-Morales1, Vishwanath Jogini, Anthony Lewis
1Department of Molecular Physiology and Biological Physics, University of Virginia, 1300 JPA, Charlottesville, Virginia 22908, USA.
Nature Structural & Molecular Biology
|October 9, 2007
Summary
Potassium (K+) channel C-type inactivation is controlled by hydrogen bonds in the selectivity filter. Stronger interactions between specific residues (Glu71 and Asp80) stabilize this inactivated state, impacting cellular excitability.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Potassium channels are crucial for cellular excitability.
- Slow inactivation, specifically C-type inactivation, is a key regulatory mechanism for K+ channel function.
- Understanding the molecular basis of C-type inactivation is essential for comprehending cellular excitability.
Purpose of the Study:
- To elucidate the molecular determinants of C-type inactivation in potassium channels.
- To investigate the role of hydrogen bonding within the selectivity filter and pore helix.
- To establish a physical framework for C-type inactivation applicable to various K+ channels.
Main Methods:
- Utilized the prokaryotic proton-gated K+ channel KcsA as a model system.
- Analyzed the impact of hydrogen bond number and strength between selectivity filter residues and the pore helix.
- Investigated residue interactions at positions Glu71 and Asp80.
- Performed engineering studies on the eukaryotic voltage-dependent K+ channel Kv1.2.
Main Results:
- Hydrogen bond interactions between selectivity filter residues and the pore helix dictate C-type inactivation rate and extent.
- Activation leads to interactions between Glu71 and Asp80, causing pore constriction and abrogating ion conduction.
- A quantitative correlation exists between interaction strength and inactivated state stability.
- Similar principles were observed in the Kv1.2 channel, suggesting broad applicability.
Conclusions:
- The number and strength of hydrogen bonds in the KcsA channel's selectivity filter control C-type inactivation.
- Specific residue interactions (Glu71-Asp80) are critical for pore constriction and channel inactivation.
- The findings provide a mechanistic understanding of C-type inactivation applicable to diverse potassium channels.
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