title: 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 KVchannel 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 Phe332into Tyr mimics the effects of PiMA on V1/2and T1/2Dand 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 Phe332in S5 of KV1.1-KV2.1 channels may be critical for the effects of PiMA, providing beneficial information for drug development of KVchannel openers.
authors.affiliation: Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan; Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.affiliation: Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan; Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
authors.affiliation: Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan; Laboratory Cellular Pharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
authors.affiliation: Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan. Electronic address: yimaizum@phar.nagoya-cu.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Imaizumi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology
chemical_list: D004224:Diterpenes; D024642:Potassium Channels, Voltage-Gated; C008911:pimaric acid; D002118:Calcium
keywords: Ca(2+)-activated K(+) channel; Channel gating; K(+) channel opener; Rosin acid; Voltage-gated K(+) channel