Block of cloned Kv4.3 potassium channels by dapoxetine

Dapoxetine, a short-acting selective serotonin reuptake inhibitor, is widely prescribed for the treatment of patients with premature ejaculation. The effects of dapoxetine were examined on cloned Kv4.3 channels stably expressed in Chinese hamster ovary cells using the whole-cell patch-clamp technique. Dapoxetine not only reduced the peak amplitude of Kv4.3 currents but also accelerated the decay rate of current inactivation in a concentration-dependent manner. Thus, the concentration-dependent reduction in Kv4.3 was measured from the integral of the current during the depolarizing pulse. Dapoxetine decreased the integral of the Kv4.3 currents over the duration of a depolarizing pulse with an IC50 of 5.3 μM. Analysis of the time dependence of the block gave estimates of an association rate constant (k+1) of 3.9 μM−1 s−1 and a dissociation rate constant (k−1) of 25.6 s−1. The KD (k−1/k+1) was 6.5 μM, similar to the IC50 value calculated from the concentration–response curve. The block of Kv4.3 by dapoxetine was highly voltage-dependent at a membrane potential coinciding with the activation of the channels. The additional block by dapoxetine displayed a shallow voltage dependence (δ = 0.21) in the full activation voltage range. The steady-state inactivation curves were shifted in the hyperpolarizing direction in the presence of dapoxetine. Dapoxetine also caused a substantial acceleration in closed-state inactivation. Dapoxetine produced a significant use-dependent block, which was accompanied by a delayed recovery from inactivation of Kv4.3 currents. These results indicated that dapoxetine potently blocks Kv4.3 currents by both preferentially binding to the open state of the channels and accelerating the closed-state inactivation. These data could provide insight into the mechanism underlying some of the therapeutic actions of this drug.

► We studied the effect of dapoxetine on Kv4.3 using whole-cell patch-clamp technique.
► Dapoxetine blocks Kv4.3 in a concentration-dependent manner.
► The block of Kv4.3 by dapoxetine was time-, voltage-, and use-dependent.
► Dapoxetine potently blocks Kv4.3 by binding to the open state of channels.
► The data help explain the mechanism underlying the therapeutic actions of this drug.