Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli

摘要: Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations produce several pain syndromes, including inherited erythromelalgia (IEM), disorder which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning triggered by warmth, the effects increased temperature on DRG expressing mutant channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we studied newly identified mutation, Ala1632Gly, multigeneration family IEM. Structural modeling suggests that Ala1632 molecular hinge Ala1632Gly mutation may affect gating. Voltage-clamp recordings revealed Nav1.7-A1632G hyperpolarizes activation depolarizes fast-inactivation, both attributes at level. Whole-cell current-clamp demonstrated spontaneous firing, lower current threshold, enhanced evoked firing rat channels. Multielectrode further intact are more active than those WT We also showed physiologically relevant thermal stimuli markedly increase mean frequencies number channels, whereas same only these parameters slightly The response upon cellular basis for warmth-triggered SIGNIFICANCE STATEMENT Inherited severe syndrome characterized caused Nav1.7, preferentially expressed sensory sympathetic neurons. More 20 patients, but question how warmth triggers has addressed. Combining array, assessed (Nav1.7-A1632G) family. Our data demonstrate level differential excitability suggesting mechanism patients.