{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:50:42Z","timestamp":1791903042095,"version":"4.3.4"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2007,6,6]],"date-time":"2007-06-06T00:00:00Z","timestamp":1181088000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2007,6,15]]},"abstract":"<jats:p>Mutations in the TTX\u2010sensitive voltage\u2010gated sodium channel subtype Na<jats:sub>v<\/jats:sub>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 Na<jats:sub>v<\/jats:sub>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\u2010state 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<jats:sub>v<\/jats:sub>1.7\u2010N395K channel. We show that the N395K mutation attenuates the inhibitory effects of lidocaine on both resting and inactivated Na<jats:sub>v<\/jats:sub>1.7. The IC<jats:sub>50<\/jats:sub> for lidocaine was estimated at 500 \u03bc<jats:sc>m<\/jats:sc> for inactivated wild\u2010type Na<jats:sub>v<\/jats:sub>1.7 and 2.8 m<jats:sc>m<\/jats:sc> for inactivated Na<jats:sub>v<\/jats:sub>1.7\u2010N395K. The N395K mutation also significantly reduced use\u2010dependent inhibition of lidocaine on Na<jats:sub>v<\/jats:sub>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 Na<jats:sub>v<\/jats:sub>1.7 current. Our observation of reduced lidocaine inhibition on Na<jats:sub>v<\/jats:sub>1.7\u2010N395K shows that the residue N395 is critical for lidocaine binding to Na<jats:sub>v<\/jats:sub>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.<\/jats:p>","DOI":"10.1113\/jphysiol.2006.127027","type":"journal-article","created":{"date-parts":[[2007,4,13]],"date-time":"2007-04-13T00:24:24Z","timestamp":1176423864000},"page":"1019-1031","source":"Crossref","is-referenced-by-count":166,"title":["A Na<sub>v<\/sub>1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity"],"prefix":"10.1113","volume":"581","author":[{"given":"Patrick L.","family":"Sheets","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"James 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