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Properties of human brain sodium channel α‐subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine
Author(s) -
Qiao Xin,
Sun Guangchun,
Clare Jeffrey J,
Werkman Taco R,
Wadman Wytse J
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12534
Subject(s) - lamotrigine , carbamazepine , phenytoin , chemistry , protein subunit , hek 293 cells , sodium channel , anticonvulsant , pharmacology , biophysics , epilepsy , biochemistry , neuroscience , biology , receptor , sodium , organic chemistry , gene
Background and purpose Voltage‐activated Na + channels contain one distinct α‐subunit. In the brain Na V 1.1, Na V 1.2, Na V 1.3 and Na V 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. Experimental approach Na + currents were recorded in voltage‐clamp mode in HEK293 cells stably expressing one of the four α‐subunits. Key results Na V 1.2 and Na V 1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and Na V 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 Na V 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 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.