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      Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States

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          Abstract

          Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at −120 mV (3% inhibition by 100 µM lacosamide) but greatly enhanced at −80 mV (43% inhibition by 100 µM lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at −120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at −40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µM lidocaine or 300 µM carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding.

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          Author and article information

          Journal
          Mol Pharmacol
          Mol. Pharmacol
          molpharm
          Mol Pharmacol
          MolPharm
          Molecular Pharmacology
          The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
          0026-895X
          1521-0111
          April 2017
          April 2017
          1 April 2018
          : 91
          : 4
          : 277-286
          Affiliations
          [1]Department of Neurobiology, Harvard Medical School, Boston Massachusetts
          Author notes
          Address correspondence to: Bruce P. Bean, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston MA 02115. E-mail: bruce_bean@ 123456hms.harvard.edu
          Article
          PMC5363714 PMC5363714 5363714 MOL_106401
          10.1124/mol.116.106401
          5363714
          28119481
          91db531b-ed03-4b7f-a07f-ec84c039a913
          Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
          Page count
          Figures: 7, Tables: 0, Equations: 0, References: 43, Pages: 10
          Categories
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          v1

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