Molecular mechanisms underlying pimaric acid-induced modulation of voltage-gated K⁺ channels

Voltage-gated K⁺ (K_V) channels, which control firing and shape of action potentials in excitable cells, are supposed to be potential therapeutic targets in many types of diseases. Pimaric acid (PiMA) is a unique opener of large conductance Ca²⁺-activated K⁺ channel. Here, we report that PiMA modulates recombinant rodent K_V channel activity. The enhancement was significant at low potentials (<0 mV) but not at more positive potentials. Application of PiMA significantly shifted the voltage-activation relationships (V_1/2) of rodent K_V1.1, 1.2, 1.3, 1.4, 1.6 and 2.1 channels (K_V1.1-K_V2.1) but K_V4.3 to lower potentials and prolonged their half-decay times of the deactivation (T_1/2D). The amino acid sequence which is responsible for the difference in response to PiMA was examined between K_V1.1-K_V2.1 and K_V4.3 by site-directed mutagenesis of residues in S5 and S6 segments of Kv1.1. The point mutation of Phe³³² into Tyr mimics the effects of PiMA on V_1/2 and T_1/2D and also abolished the further change by addition of PiMA. The results indicate that PiMA enhances voltage sensitivity of K_V1.1-K_V2.1 channels and suggest that the lipophilic residues including Phe³³² in S5 of K_V1.1-K_V2.1 channels may be critical for the effects of PiMA, providing beneficial information for drug development of K_V channel openers.