Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels

G. Liu, Vladimir Yarov-Yarovoy, M. Nobbs, J. J. Clare, T. Scheuer, W. A. Catterall

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant drugs. A receptor site for local anesthetics has been defined in transmembrane segment S6 in domain IV (IVS6) of the α subunit, but the anticonvulsant lamotrigine and related compounds have more complex structures than local anesthetics and may interact with additional amino acid residues. Apparent KD values for inactivated-state block of rat brain type IIA sodium channels expressed in Xenopus oocytes were 31.9 μM, 17.3 μM, 3.7 μM and 10.3 μM for lamotrigine and compounds 227c89, 4030w92 and 619c89, respectively. Compound 619c89 was the strongest frequency-dependent blocker, which correlated with higher affinity and a five-fold slower recovery from drug block compared to lamotrigine. Examination of lamotrigine block of mutant sodium channel α subunits, in which alanine had been substituted for each individual amino acid in IVS6, identified mutations I1760A, F1764A and Y1771A as causing the largest reductions in affinity (six-, seven- and 12-fold, respectively). The ratios of effects of these three mutations differed for compounds 227c89, 4030w92, and 619c89. The amino acid residues interacting with these pore-blocking drugs define a surface of IVS6 that is exposed to the pore and may rotate during gating.

Original languageEnglish (US)
Pages (from-to)413-422
Number of pages10
Issue number3
StatePublished - Mar 2003
Externally publishedYes


  • Analgesic
  • Anticonvulsant
  • Brain
  • Ion channel blocker
  • Sodium channels

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology


Dive into the research topics of 'Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels'. Together they form a unique fingerprint.

Cite this