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Interaction between fast and slow inactivation in Skm1 sodium channels
D E Featherstone1, J E Richmond, P C Ruben
1Department of Biology, Utah State University, Logan 84322-5305, USA. davef@cc.usu.edu
Biophysical Journal
|December 1, 1996
Summary
Fast inactivation of rat skeletal muscle sodium channels (Skm1) does not prevent slow inactivation. Removing fast inactivation enhances the speed and completeness of slow inactivation, suggesting an interaction between the two processes.
Area of Science:
- Molecular biology
- Neuroscience
- Ion channel physiology
Background:
- Sodium channels are crucial for electrical excitability in muscle and nerve.
- Skeletal muscle sodium channels (Skm1) exhibit complex inactivation kinetics, including fast and slow components.
- Understanding these inactivation mechanisms is key to comprehending cellular electrophysiology.
Purpose of the Study:
- To characterize the interplay between fast and slow inactivation in Skm1 sodium channels.
- To investigate the role of the DIII-IV inactivation loop in Skm1 channel gating.
- To determine if fast inactivation influences the subsequent slow inactivation process.
Main Methods:
- Coexpression of rat Skm1 alpha and beta 1 subunits in Xenopus oocytes.
- On-cell macropatch recordings to measure sodium currents.
- Site-directed mutagenesis (IFM1303QQQ) to selectively abolish fast inactivation.
Main Results:
- The IFM1303QQQ mutation completely eliminated fast inactivation across all voltages.
- Slow inactivation remained functional in channels lacking fast inactivation.
- Wild-type channels showed incomplete slow inactivation (~20% non-inactivating) even at positive potentials.
- Complete removal of fast inactivation accelerated and enhanced the extent of slow inactivation.
Conclusions:
- Fast inactivation acts as a gating step that can reduce the probability of subsequent slow inactivation.
- The DIII-IV inactivation loop is critical for fast inactivation but not essential for slow inactivation.
- These findings reveal a sequential relationship between fast and slow inactivation mechanisms in Skm1 sodium channels.