Sodium channel slow inactivation interferes with open channel block

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Voltage-gated sodium channel Nav1.7 mutations are associated with inherited pain disorders like erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD).
• PEPD mutations disrupt fast inactivation and increase persistent currents, while IEM mutations do not affect resurgent currents.
• The IEM deletion mutation ΔL955 enhances persistent currents but not resurgent currents, and significantly increases slow inactivation (SI).

Purpose of the Study:

• To investigate the relationship between slow inactivation (SI) and resurgent currents in Nav1.7 and Nav1.6 sodium channels.
• To determine if enhanced SI interferes with the mechanisms underlying resurgent currents.

Main Methods:

• Introduced mutations into Nav1.7 and Nav1.6 channels to modulate slow inactivation (SI) levels.
• Electrophysiological recordings to assess the impact of these mutations on channel function, specifically resurgent currents.

Main Results:

• Enhanced SI in Nav1.7 and Nav1.6 channels was correlated with impaired resurgent currents.
• The IEM deletion mutation ΔL955 demonstrated enhanced SI and reduced resurgent currents, despite increased persistent currents.

Conclusions:

• Enhanced slow inactivation (SI) negatively impacts resurgent currents in voltage-gated sodium channels.
• SI may interfere with the open-channel block mechanism essential for generating resurgent currents.
• These findings provide novel insights into the pathophysiology of inherited pain syndromes linked to Nav1.7 dysfunction.