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Low potency inhibition of NaV1.7 by externally applied QX-314 via a depolarizing shift in the voltage-dependence of activation



Klasfauseweh, Tabea;

Israel, Mathilde R;

Ragnarsson, Lotten;

Cox, James J;

Durek, Thomas;

Carter, David A;

Leffler, Andreas;

Deuis, Jennifer R; + view all

Klasfauseweh, Tabea;

Israel, Mathilde R;

Ragnarsson, Lotten;

Cox, James J;

Durek, Thomas;

Carter, David A;

Leffler, Andreas;

Vetter, Irina;

Deuis, Jennifer R;

– view fewer

(2022)

Low potency inhibition of NaV1.7 by externally applied QX-314 via a depolarizing shift in the voltage-dependence of activation.

European Journal of Pharmacology
, 925


, Article 175013. 10.1016/j.ejphar.2022.175013.


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Text (Supplementary Information)

Cox_QX-314_supplementary-material_revision_3.pdf

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Abstract

QX-314 is a quaternary permanently charged lidocaine derivative that inhibits voltage-gated sodium channels (NaV). As it is membrane impermeable, it is generally considered that QX-314 applied externally is inactive, unless it can gain access to the internal local anesthetic binding site via another entry pathway. Here, we characterized the electrophysiological effects of QX-314 on NaV1.7 heterologously expressed in HEK293 cells, and found that at high concentrations, external QX-314 inhibited NaV1.7 current (IC50 2.0 ± 0.3 mM) and shifted the voltage-dependence to more depolarized potentials (ΔV50 +10.6 mV). Unlike lidocaine, the activity of external QX-314 was not state- or use-dependent. The effect of externally applied QX-314 on NaV1.7 channel biophysics differed to that of internally applied QX-314, suggesting QX-314 has an additional externally accessible site of action. In line with this hypothesis, disruption of the local anesthetic binding site in a [F1748A]NaV1.7 mutant reduced the potency of lidocaine by 40-fold, but had no effect on the potency or activity of externally applied QX-314. Therefore, we conclude, using an expression system where QX-314 was unable to cross the membrane, that externally applied QX-314 is able to inhibit NaV1.7 peak current at low millimolar concentrations.

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