Inhibition of Kv4.3 potassium channels by trazodone

Trazodone, a triazolopyridine antidepressant, is commonly used in the treatment of depression and insomnia. Kv4.3 channels are transiently, and rapidly, inactivating Kv channels that are highly expressed in cardiac myocytes and neurons. To determine the electrophysiological basis for the cardiac and neuronal actions of trazodone, we studied the effects of trazodone on Kv4.3 currents stably expressed in Chinese hamster ovary cells using the whole-cell patch-clamp technique. Trazodone decreased the peak amplitude of Kv4.3 in a concentration-dependent manner with an IC50 of 55.4 μM. Under control conditions, the time course of inactivation of Kv4.3 at +40 mV was fitted to a double exponential function. Trazodone produced a concentration-dependent slowing of the fast and slow components of Kv4.3 inactivation during a voltage step to +40 mV. The inhibition of Kv4.3 by trazodone was voltage independent over the entire voltage range tested. Trazodone shifted the voltage dependence of the steady-state inactivation of Kv4.3 to a hyperpolarizing direction. However, the slope factor of the steady-state inactivation was not affected by trazodone. Under control conditions, the closed-state inactivation of Kv4.3 was fitted to a single exponential function. Trazodone significantly accelerated the closed-state inactivation of Kv4.3. Trazodone produced a weak use-dependent inhibition of Kv4.3 at frequencies of 1 and 2 Hz. m-Chlorophenylpiperazine (m-CPP), a major metabolite of trazodone, inhibited Kv4.3 less potently than trazodone, with an IC50 of 118.6 μM. These results suggest that trazodone preferentially inhibited Kv4.3 by both binding to the closed state and accelerating the closed-state inactivation of the channel.