Inhibition of recombinant Cav3.1 (α1G) T-type calcium channels by the antipsychotic drug clozapine

Abstract Low voltage-activated T-type calcium channels are involved in the regulation of the neuronal excitability, and could be subject to many antipsychotic drugs. The effects of clozapine, an atypical antipsychotic drug, on recombinant Ca v 3.1 T-type calcium channels heterologously expressed in human embryonic kidney 293 cells were examined using whole-cell patch-clamp recordings. At a standard holding potential of − 100 mV, clozapine inhibited Ca v 3.1 currents with an IC 50 value of 23.7 ± 1.3 μM in a use-dependent manner. However, 10 μM clozapine inhibited more than 50% of the Ca v 3.1 currents in recordings at a more physiologically relevant holding potential of −75 mV. Clozapine caused a significant hyperpolarizing shift in the steady-state inactivation curve of the Ca v 3.1 channels, which is presumably the main mechanism accounting for the inhibition of the Ca v 3.1 currents. In addition, clozapine slowed Ca v 3.1 deactivation and inactivation kinetics but not activation kinetics. Clozapine-induced changes in deactivation and inactivation rates of the Ca v 3.1 channel gating would likely facilitate calcium influx via Ca v 3.1 T-type calcium channels. Thus, clozapine may exert its therapeutic and/or side effects by altering cell's excitability and firing properties through actions on T-type calcium channels.