Abstract
Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). PEPD mutations impair Nav1.7 fast inactivation and increase persistent currents. PEPD mutations also increase resurgent currents, which involve the voltage-dependent release of an open channel blocker. In contrast, IEM mutations, whenever tested, leave resurgent currents unchanged. Accordingly, the IEM deletion mutation L955 (ΔL955) fails to produce resurgent currents despite enhanced persistent currents, which have hitherto been considered a prerequisite for resurgent currents. Additionally, ΔL955 exhibits a prominent enhancement of slow inactivation (SI). We introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair SI in order to investigate their effects on resurgent currents. Our results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block.
Highlights
Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD)
The Nav1.7 subtype is predominantly expressed in sensory dorsal root ganglion neurons (DRGs) and mutations leading to hyperexcitability cause the severe neuropathic pain syndromes inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD) and small-fiber neuropathy (SFN)[1]
Mutagenesis studies have linked both diseases to apparently different pathomechanisms: most IEM mutations discovered to date show a significant hyperpolarizing shift in the voltage dependence of activation whereas all characterized PEPD mutations induce a depolarizing shift of steady-state fast inactivation
Summary
Unlike recovery from fast inactivation, which involves transition of the pore from the open to closed state[7], the endogenous blocker can be expelled from the open-state pore during repolarization This voltage-dependent release of open channel block can generate a resurgent current during the falling phase of an action potential. All PEPD mutations tested so far show enhanced resurgent currents[1] whereas all IEM mutations tested to date did not increase resurgent currents This difference together with altered persistent currents has been proposed to be an electrophysiological basis for the distinct clinical picture of these two diseases[8]. It is not well understood why PEPD mutations enhance resurgent currents and IEM mutations do not. Our results suggest a new regulatory mechanism for resurgent currents, namely that SI interferes with open channel block
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