Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents

Area of Science:

• Neuroscience
• Molecular Biology
• Physiology

Background:

• Voltage-gated sodium channels (Nav) are crucial for action potential generation in excitable tissues.
• Mutations in Nav genes cause inherited channelopathies, some with temperature-sensitive phenotypes like pain syndromes.
• Understanding temperature's role in channelopathies is limited due to studies often being at room temperature.

Purpose of the Study:

• To investigate the temperature sensitivity of four Nav subtypes (Nav1.3, Nav1.5, Nav1.6, Nav1.7).
• To examine the effects of temperature on two Nav1.7 mutations linked to inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD).

Main Methods:

• Utilized an automated patch clamp system to express and record from human embryonic kidney cells.
• Tested Nav subtype and mutation function at three temperatures: 15°C, 25°C, and 35°C.

Main Results:

• Increased temperature shifted the voltage dependence of activation to more hyperpolarized potentials across all tested Nav subtypes.
• Nav1.3 showed significantly slowed inactivation at 15°C, leading to increased persistent current and potential cold-induced hyperexcitability.
• The impaired fast inactivation in the Nav1.7/I1461T mutation (PEPD) was notably worsened at 15°C.

Conclusions:

• Temperature significantly modulates Nav channel gating in a subtype-specific manner.
• Cooling exacerbates the gating defects caused by specific Nav1.7 mutations, impacting cellular excitability.
• Temperature should be considered a critical factor in understanding channelopathies and their disease phenotypes.