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(V)1.1, 1.2, 1.3, 1.4, 1.6 and 2.1 channels (K(V)1.1-K(V)2.1) but K(V)4.3 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(V)1.1-K(V)2.1 and K(V)4.3 by site-directed mutagenesis of residues in S5 and S6 segments of Kv1.1. The point mutation of Phe(332) 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(V)1.1-K(V)2.1 channels and suggest that the lipophilic residues including Phe(332) in S5 of K(V)1.1-K(V)2.1 channels may be critical for the effects of PiMA, providing beneficial information for drug development of K-V channel openers. (C) 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.