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

Abstract

Voltage-gated K+ (KV) 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 KV 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 (V1/2) of rodent KV1.1, 1.2, 1.3, 1.4, 1.6 and 2.1 channels (KV1.1–KV2.1) but KV4.3 to lower potentials and prolonged their half-decay times of the deactivation (T1/2D). The amino acid sequence which is responsible for the difference in response to PiMA was examined between KV1.1–KV2.1 and KV4.3 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 V1/2 and T1/2D and also abolished the further change by addition of PiMA. The results indicate that PiMA enhances voltage sensitivity of KV1.1–KV2.1 channels and suggest that the lipophilic residues including Phe332 in S5 of KV1.1–KV2.1 channels may be critical for the effects of PiMA, providing beneficial information for drug development of KV channel openers.