Contributed equally as first author.
Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine
Version of Record online: 24 JAN 2014
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Midkine. Guest Editors: Takashi Muramatsu and Kenji Kadomatsu
Volume 171, Issue 4, pages 1054–1067, February 2014
How to Cite
Qiao, X., Sun, G., Clare, J. J., Werkman, T. R. and Wadman, W. J. (2014), Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine. British Journal of Pharmacology, 171: 1054–1067. doi: 10.1111/bph.12534
- Issue online: 24 JAN 2014
- Version of Record online: 24 JAN 2014
- Accepted manuscript online: 27 NOV 2013 11:45PM EST
- Manuscript Accepted: 21 NOV 2013
- Manuscript Revised: 8 NOV 2013
- Manuscript Received: 9 JUL 2013
- Dutch National Epilepsy Foundation. Grant Number: 06-13
- ‘Platform alternatief voor dierproeven’. Grant Number: 114000091
- sodium channel;
- antiepileptic drug
Background and purpose
Voltage-activated Na+ channels contain one distinct α-subunit. In the brain NaV1.1, NaV1.2, NaV1.3 and NaV1.6 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.
Na+ currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits.
NaV1.2 and NaV1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV1.1 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 NaV1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin.
Conclusions and implications
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.