Key result
Cariprazine concentration-dependently inhibited hERG 1A and hERG 1A/3.1 currents with IC50 values of 4.1 and 12.2 μM, respectively, by preferentially interacting with the open states of the channel.
Why the study?
Cariprazine is an atypical antipsychotic widely used for schizophrenia and bipolar mania, but its biophysical effects on hERG potassium channels required investigation.
Does cariprazine inhibit hERG 1A and hERG 1A/3.1 potassium channels in HEK cells?
Does cariprazine inhibit hERG 1A and hERG 1A/3.1 potassium channels in HEK cells?
Cariprazine concentration-dependently inhibits hERG 1A and hERG 1A/3.1 currents by interacting with the open states of the channel, providing important biophysical data for assessing its potential cardiac safety profile.
May inform cariprazine cardiac safety evaluation; leaves open clinical QT risk translation.
Cariprazine is a novel atypical antipsychotic drug that is widely used for the treatment of schizophrenia and bipolar mania/mixed disorder. We used the whole-cell patch-clamp technique to investigate the effects of cariprazine on hERG channels that are stably expressed in HEK cells. Cariprazine inhibited the hERG 1A and hERG 1A/3.1 tail currents at −50 mV in a concentration-dependent manner with IC50 values of 4.1 and 12.2 μM, respectively. The block of hERG 1A currents by cariprazine was voltage-dependent, and increased over a range of voltage for channel activation. Cariprazine shifted the steady-state inactivation curve of the hERG 1A currents in a hyperpolarizing direction and produced a use-dependent block. A fast application of cariprazine inhibited the hERG 1A currents elicited by a 5 s depolarizing pulse to +60 mV to fully inactivate the hERG 1A currents. During a repolarizing pulse wherein the hERG 1A current was deactivated slowly, cariprazine rapidly and reversibly blocked the open state of the hERG 1A current. However, cariprazine did not affect hERG 1A and hERG 1A/3.1 channel trafficking to the cell membrane. Our results indicated that cariprazine concentration-dependently inhibited hERG 1A and hERG 1A/3.1 currents by preferentially interacting with the open states of the hERG 1A channel, but not by the disruption of hERG 1A and hERG 1A/3.1 channel protein trafficking. Our study examined cariprazine's mechanism of action provides a biophysical profile that is necessary to assess the potential therapeutic effects of this drug.
No takes yet. Share an insight, caveat, or question.
Lee et al. (2019) studied this question. Cariprazine was evaluated on Inhibition of hERG 1A and hERG 1A/3.1 tail currents (IC50 4.1 and 12.2 μM). Cariprazine concentration-dependently inhibited hERG 1A and hERG 1A/3.1 currents with IC50 values of 4.1 and 12.2 μM, respectively, by preferentially interacting with the open states of the channel.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: