Automatic estimation of hNaV1.5 channel inactivation improves pharmacological evaluation using the new adaptive protocol feature on Qube


Safety Pharmacology Society 2019


Anders Lindqvist



The human sodium channel hNaV1.5, encoded by the SCN5A gene, is crucial for the cardiac action potential upstroke and subsequent signal propagation in the heart. Inhibition of the sodium current by drugs decreases the rate of cardiomyocyte depolarization and the conduction velocity which may lead to serious implications. For these reasons, off-target effects on hNaV1.5 are considered a risk marker for drug candidates and the hNaV1.5 is one of the most used in vitro assays in cardiac safety testing and is also one of the most important currents in the CiPA paradigm.

Several drugs, known to inhibit the hNaV1.5 channel, are either use- or state-dependent and preferentially bind to the open and inactivated state, respectively. When experimenting on voltage-gated ion channels, it is imperative that the voltage applied to the cells is accurate. This is especially important when testing state-dependent compounds. In order to determine compound activity in the most accurate way, all tested cells should have an identical degree of inactivation, a state that will not be achieved by using the same voltage to all experiment sites but rather individual voltages adjusted to the cell’s individual biophysical properties need to be applied.
The Qube, as well as the new QPatch II, are high-throughput automated patch clamp platforms, suitable for studying a wide range of ion channels. Both systems are equipped with the option to run online adaptive protocols, which makes it possible to set each individual cell to a user-defined level of inactivation, e.g. the half-inactivation potential (V½) and use that value subsequently in e.g. a preconditioning pulse. Applying this new adaptive protocol feature, we determined NaV1.5 IC50 values for both the open and the inactivated state for a set of known sodium channel inhibitors. We could show that the use of individual V½ reduces data variability compared to standard methods and thereby improves the accuracy of drug evaluation.

Keywords: Adaptive voltage clamp

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