Imiquimod enhances excitability of dorsal root ganglion neurons by inhibiting background (K2P) and voltage-gated (Kv1.1 and Kv1.2) potassium channels

When IQ was applied to DRG neurons, we observed an increase in action potential (AP) duration and membrane resistance both in wild type and TLR7-deficient mice. Based on these results, we tested whether the treatment of IQ has an effect on the activity of K+ channels, Kv1.1 and Kv1.2 (voltage-gated K+ channels) and TREK1 and TRAAK (K2P channels). IQ effectively reduced the currents mediated by both K+ channels in a dose-dependent manner, acting as an antagonist at TREK1 and TRAAK and as a partial antagonist at Kv1.1 and Kv1.2.Our results demonstrate that IQ blocks the voltage-gated K+ channels to increase AP duration and K2P channels to increase membrane resistance, which are critical for the membrane excitability of DRG neurons. Therefore, we propose that IQ enhances the excitability of DRG neurons by blocking multiple potassium channels and causing pruritus.Imiquimod (IQ) is widely used to treat various skin diseases such as molluscum contagiosum, basal cell carcinoma, and Bowen's disease [1]. Topical application of the compound is currently approved for treatment of genital warts, a highly contagious sexually transmitted disease caused by human papillomavirus [1-5]. It is believed that IQ modulates immune responses via Toll-like receptor 7 (TLR7) releasing IFN-α/β and proinflammatory cytokines [6]. Nevertheless, the exact mechanism of how IQ activates the immune system is not fully understood. Despite its clinical importance, the most prominent side effect of IQ is pruritus, e.g. itching sensation [7,8]. The mechanism of how IQ causes itching sensation has remained unknown.Recently we and others reported that IQ-induced depolarization in dorsal root ganglion (DRG) neurons leads to itching behavior [7,8]. Even though these two studies agreed upon IQ's action on the cellular and behavioral level, there was a profound discrepancy on the molecular target of IQ. The study by Liu et al. reported that membrane depolarization caused by IQ required TLR7 to generate action