@article{a9f1eeb3e7c84d71baf82841e9dc7828,
title = "Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy",
abstract = "Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Na(v)1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Na(v)1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Na(v)1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 JIM, lacosamide acts as a potent sodium channel inhibitor of Na(v)1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Na(v)1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Na(v)1.7 variants.",
keywords = "small fibre neuropathy, lacosamide, Na(v)1.7 mutations, neuropathic pain, electrophysiology, VOLTAGE-GATED SODIUM, MOLECULAR DETERMINANTS, SLOW-INACTIVATION, NA+ CHANNELS, PAIN, MUTATION, BINDING, INHIBITION, EFFICACY, NEURONS",
author = "Labau, {Julie I. R.} and Mark Estacion and Tanaka, {Brian S.} and {de Greef}, {Bianca T. A.} and Hoeijmakers, {Janneke G. J.} and Margot Geerts and Gerrits, {Monique M.} and Smeets, {Hubert J. M.} and Faber, {Catharina G.} and Merkies, {Ingemar S. J.} and Giuseppe Lauria and Dib-Hajj, {Sulayman D.} and Waxman, {Stephen G.}",
note = "Funding Information: This work was supported by Center Grant B9253-C from the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service. This project also received funding from the Molecule-to-Man Pain Network, a European Commission Multi-Center Collaborative Projects through the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement No. 721841. The clinical study was supported by a grant from the Prinses Beatrix Spierfonds. The Center for Neuroscience and Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University. Funding Information: This work was supported by Center Grant B9253-C from the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service. This project also received funding from the Molecule-to-Man Pain Network, a European Commission Multi-Center Collaborative Projects through the European Union's Horizon 2020 research and innovation program under grant agreement No. 721841. The clinical study was supported by a grant from the Prinses Beatrix Spierfonds. The Center for Neuroscience and Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University. Publisher Copyright: {\textcopyright} The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2020",
month = mar,
doi = "10.1093/brain/awaa016",
language = "English",
volume = "143",
pages = "771--782",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
}