NaV1.5 - "NaV1.5-ΔKPQ late INa current properties and pharmacology on the SyncroPatch 384i"

icon sp96   SyncroPatch 384i (a predecessor model of the SyncroPatch 384) application note   logo pdf (1.5 MB)
Cells were kindly provided by Metrion Biosciences.


The cardiac late Na current (late INa) generates persistent currents throughout the plateau phase of the cardiac action potential. Several mutations in the SCN5A gene cause a form of hereditary long QT syndrome (LQT3)1-3. The ΔKPQ mutation deletes residues Lys 1505, Pro 1506 and Gln 1507, resulting in a sustained, non-inactivating current during long (over 50 ms) depolarizations1,2. This sustained current causes prolongation of the action potential which can result in fatal ventricular arrhythmias such as Torsade de Pointes (TdP)1.

One aim of the Comprehensive In Vitro Pro-arrhythmia Assay (CiPA) initiative is to improve drug safety testing in pre-clinical development by evaluating the pro-arrhythmic risk of a compound4,5. Validation studies confirm that testing the effect of compounds on an increased number of human cardiac ion channel currents including INa (NaV1.5 peak and late current) as well as IKr (hERG) leads to improved prediction of their clinical risk. Late INa can be recorded in WT NaV1.5 channels using the toxin ATX-II or veratridine, or using a cell line with LQT3 mutations in NaV1.5 without the need for pharmacological enhancement. The latter might also reduce the risk of cross-reactions between late-current enhancers and test compounds.

Here we present data collected on the Syncro- Patch 384i showing the peak and late INa current re¬corded from WT and NaV1.5-ΔKPQ cell lines. Peak current could be reliably recorded from both cell types. In WT cells, late INa was negligible in the absence of ATX-II, whereas the late INa from NaV1.5-ΔKPQ cells could be reliably recorded. Peak current from WT, and peak and late INa from NaV1.5-ΔKPQ was inhibited by ranolazine and mexiletine and IC50 values agreed well with the literature6.

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