Chlorpromazine directly inhibits Kv1.3 channels by facilitating the inactivation of channels

Kv1.3 channels in microglia are pivotal in regulating neuroinflammation. The antipsychotic chlorpromazine (CPZ) demonstrates anti-inflammatory effects by decreasing Kv1.3 activity in mPFC microglia. However, the precise mechanism of CPZ's effect in the mPFC remains unclear, given that CPZ is known to inhibit dopamine receptors and the mPFC contains various cell types with dopamine receptors. In this study, we investigate how CPZ inhibits Kv1.3 channels using human Kv1.3 channel-expressing Xenopus laevis oocytes. CPZ directly inhibits Kv1.3 channel currents in a concentration-dependent manner. The CPZ-mediated Kv1.3 channel inhibition is not voltage-dependent, and CPZ accelerates Kv1.3 channel inactivation without significantly affecting its activation. Our findings suggest that CPZ directly blocks Kv1.3 channels without involving other ion channels or receptors, including dopamine receptors, thereby contributing to the understanding of its neuroinflammation-suppressing mechanism.