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This Article Full Text Full Text (PDF) Supplemental data All Versions of this Article: 581/3/1019    most recent jphysiol.2006.127027v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sheets, P. L. Articles by Cummins, T. R. Search for Related Content PubMed PubMed Citation Articles by Sheets, P. L. Articles by Cummins, T. R. Related Collections Neuroscience

¹ Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
² Department of Neurology
³ Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA
⁴ Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, CT 06516, USA

Mutations in the TTX-sensitive voltage-gated sodium channel subtype Na_v1.7 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 Na_v1.7 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 Na_v1.7-N395K channel. We show that the N395K mutation attenuates the inhibitory effects of lidocaine on both resting and inactivated Na_v1.7. The IC₅₀ for lidocaine was estimated at 500 µM for inactivated wild-type Na_v1.7 and 2.8 mM for inactivated Na_v1.7-N395K. The N395K mutation also significantly reduced use-dependent inhibition of lidocaine on Na_v1.7 current. In contrast, a different hereditary erythromelalgia mutation (F216S), not located in the local anaesthetic binding site, had no effect on lidocaine inhibition of Na_v1.7 current. Our observation of reduced lidocaine inhibition on Na_v1.7-N395K shows that the residue N395 is critical for lidocaine binding to Na_v1.7 and suggests that the response of individuals with hereditary erythromelalgia to lidocaine treatment may be determined, at least in part, by their specific genotype.

(Received 21 December 2006; accepted after revision 2 April 2007; first published online 12 April 2007)
Corresponding author T. R. Cummins: Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, 950 West Walnut St, R2 468, Indianapolis, IN 46202, USA. Email: trcummin{at}iupui.edu.

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