Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

Abstract

Inherited erythromelalgia/erythermalgia (IEM) is a neuropathy characterized by pain and redness of the extremities that is triggered by warmth. IEM has been associated with missense mutations of the voltage-gated sodium channel Na v 1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Na v 1.7, with only two mutations in segment 4 (S4) and S6 of domain I. We report here a simplex case with an alanine 863 substitution by proline (A863P) in S5 of domain II of Na v 1.7. The functional effect of A863P was investigated by voltage-clamp analysis in human embryonic kidney 293 cells and by current-clamp analysis to determine the effects of A863P on firing properties of small DRG neurons. Activation of mutant channels was shifted by Ϫ8 mV, whereas steady-state fast inactivation was shifted by ϩ10 mV, compared with wild-type (WT) channels. There was a marked decrease in the rate of deactivation of mutant channels, and currents elicited by slow ramp depolarizations were 12 times larger than for WT. These results suggested that A863P could render DRG neurons hyperexcitable. We tested this hypothesis by studying properties of rat DRG neurons transfected with either A863P or WT channels. A863P depolarized resting potential of DRG neurons by ϩ6 mV compared with WT channels, reduced the threshold for triggering single action potentials to 63% of that for WT channels, and increased firing frequency of neurons when stimulated with suprathreshold stimuli. Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM.

NaV1.7 Gain-of-Function Mutations as a Continuum: A1632E Displays Physiological Changes Associated with Erythromelalgia and Paroxysmal Extreme Pain Disorder Mutations and Produces Symptoms of Both Disorders

“…Previously described PEPD mutations have been shown to impair inactivation and have not been reported to affect activation or deactivation (Fertleman et al, 2006;Jarecki et al, 2008). In contrast, mutations linked to IEM have been observed to hyperpolarize activation and slow deactivation, either without an effect on inactivation (Cummins et al, 2004;Choi et al, 2006;Lampert et al, 2006;Sheets et al, 2007;Cheng et al, 2008) or coupled to a shift in inactivation voltage dependence, which was, nevertheless, complete (Dib-Hajj et al, 2005;Han et al, 2006;Harty et al, 2006). The shifts of voltage dependence of activation and fast inactivation for these PEPD and IEM mutants are illustrated in Figure 8.…”

Continuous -Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (NaV1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy

“…Among sodium channel isoforms, Na V 1.7 is of particular interest because of emerging evidence from genetic studies that correlate alterations in Na V 1.7 with human syndromes characterized by spontaneous pain (Yang et al, 2004;Choi et al, 2006;Fertleman et al, 2006). Mutations in the coding sequence of Na V 1.7 that result in channels that are electrically hyperexcitable produce a painful condition (Harty et al, 2006), and it has been shown that an increase in the number of channels present in the membrane of DRG neurons can lead to a similar state of hyperexcitability of the primary nociceptive afferent (Devor, 2006).…”

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

“…26 currents. 30,31 The Na V currents were recorded in response to every stimulation potential from -70 to +50 mV in 10 mV increments.…”