A Nav 1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity

Patrick L. Sheets, James O. Jackson, Stephen G. Waxman, Sulayman D. Dib-hajj, Theodore R. Cummins

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

Mutations in the TTX-sensitive voltage-gated sodium channel subtype Nav 1.7 have been implicated in the painful inherited neuropathy, hereditary erythromelalgia. Hereditary erythromelalgia can be difficult to treat and, although sodium channels are targeted by local anaesthetics such as lidocaine (lignocaine), some patients do not respond to treatment with local anaesthetics. This study examined electrophysiological differences in Nav 1.7 caused by a hereditary erythromelalgia mutation (N395K) that lies within the local anaesthetic binding site of the channel. The N395K mutation produced a hyperpolarized voltage dependence of activation, slower kinetics of deactivation, and impaired steady-state slow inactivation. Computer simulations indicate that the shift in activation is the major determinant of the hyperexcitability induced by erythromelalgia mutations in sensory neurons, but that changes in slow inactivation can modulate the overall impact on excitability. This study also investigated lidocaine inhibition of the Nav 1.7-N395K channel. We show that the N395K mutation attenuates the inhibitory effects of lidocaine on both resting and inactivated Nav 1.7. The IC50 for lidocaine was estimated at 500 μM for inactivated wild-type Nav 1.7 and 2.8 mM for inactivated Nav 1.7-N395K. The N395K mutation also significantly reduced use-dependent inhibition of lidocaine on Nav 1.7 current. In contrast, a different hereditary erythromelalgia mutation (F216S), not located in the local anaesthetic binding site, had no effect on lidocaine inhibition of Nav 1.7 current. Our observation of reduced lidocaine inhibition on Nav 1.7-N395K shows that the residue N395 is critical for lidocaine binding to Nav 1.7 and suggests that the response of individuals with hereditary erythromelalgia to lidocaine treatment may be determined, at least in part, by their specific genotype.

Original languageEnglish (US)
Pages (from-to)1019-1031
Number of pages13
JournalJournal of Physiology
Volume581
Issue number3
DOIs
StatePublished - Jun 1 2007

ASJC Scopus subject areas

  • Physiology

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