title: Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine.
abstract: OBJECTIVE
  Voltage-activated Na(+) channels contain one distinct α-subunit. In the brain NaV 1.1, NaV 1.2, NaV 1.3 and NaV 1.6 are the four most abundantly expressed α-subunits. The antiepileptic drugs (AEDs) carbamazepine, phenytoin and lamotrigine have voltage-gated Na(+) channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four α-subunits and characterizes their interaction with carbamazepine, phenytoin and lamotrigine.
  
  
  METHODS
  Na(+) currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits.
  
  
  RESULTS
  NaV 1.2 and NaV 1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV 1.1 subunits generate the largest window current. Lamotrigine evokes a larger maximal shift of the steady-state inactivation relationship than carbamazepine or phenytoin. Carbamazepine shows the highest binding rate to the α-subunits. Lamotrigine binding to NaV 1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin.
  
  
  CONCLUSIONS
  The four Na(+) channel α-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na(+) channel subunits. Particularly, lamotrigine binding to the four α-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. Knowledge of the biophysical and binding parameters could be employed to optimize therapeutic strategies and drug development.
authors.affiliation: Center for NeuroScience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.forename: Guangchun
authors.initials: G
authors.lastname: Sun
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Clare
authors.forename: Taco R
authors.initials: TR
authors.lastname: Werkman
authors.forename: Wytse J
authors.initials: WJ
authors.lastname: Wadman
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000502:physiology; D002220:Carbamazepine / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D000077213:Lamotrigine; D010672:Phenytoin / Q000494:pharmacology; D021122:Protein Subunits / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology*; D014227:Triazines / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D021122:Protein Subunits; D015222:Sodium Channels; D014227:Triazines; D061567:Voltage-Gated Sodium Channel Blockers; D002220:Carbamazepine; D010672:Phenytoin; D000077213:Lamotrigine
keywords: antiepileptic drug; carbamazepine; epilepsy; lamotrigine; phenytoin; sodium channel