Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel

Area of Science:

• Molecular Biology
• Biophysics
• Cardiovascular Physiology

Background:

• The voltage-sensitive sodium channel Na(v)1.5, encoded by SCN5A, is crucial for electrical activity in the heart.
• Na(v)1.5 is known to be mechanosensitive, but the molecular basis of this sensitivity is not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying the mechanosensitivity of the Na(v)1.5 channel.
• To investigate how mechanical forces modulate Na(v)1.5 channel gating kinetics and voltage dependence.

Main Methods:

• Heterologous expression of Na(v)1.5 in HEK 293 cells.
• Electrophysiological recordings using cell-attached patch-clamp techniques.
• Application of mechanical pressure to cell-attached patches to assess channel function.

Main Results:

• Mechanical stretch induced dose-dependent hyperpolarizing shifts in the voltage dependence of Na(v)1.5 activation and inactivation (∼0.7 mV mmHg(-1)).
• Stretch accelerated voltage sensor movement but not the rate constants for gate opening or fast inactivation.
• Stretch stabilized inactivated states, slowing recovery from inactivation, and increased peak current by recruiting more active channels.

Conclusions:

• Mechanical forces modulate Na(v)1.5 channel gating primarily by altering voltage sensor movement.
• These findings provide molecular insights into how mechanical stimuli influence cardiac electrophysiology via Na(v)1.5.
• The mechanosensitivity of Na(v)1.5 may play a significant role in electromechanical coupling and cardiac mechanotransduction.