Inhibition of Kv2.1 potassium channels by the antidepressant drug sertraline

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In this study, we have used the patch-clamp technique to assess the effects of sertraline on Kv2.1 channels heterologously expressed in HEK-293 cells and on the voltage-gated potassium currents (I_Kv) of Neuro 2a cells, which are predominantly mediated by Kv2.1 channels. Our results reveal that sertraline inhibits Kv2.1 channels in a concentration-dependent manner. The sertraline-induced inhibition was not voltage-dependent and did not require the channels to be open. The kinetics of activation and deactivation were accelerated and decelerated, respectively, by sertraline. Moreover, the inhibition by this drug was use-dependent. Notably, sertraline significantly modified the inactivation mechanism of Kv2.1 channels; the steady-state inactivation was shifted to hyperpolarized potentials, the closed-state inactivation was enhanced and accelerated, and the recovery from inactivation was slowed, suggesting that this is the main mechanism by which sertraline inhibits Kv2.1 channels. Overall, this study provides novel insights into the pharmacological actions of sertraline on Kv2.1 channels, shedding light on the intricate interaction between SSRIs and ion channel function.