title: Evaluation of gambierol and its analogs for their inhibition of human Kv1.2 and cytotoxicity.
abstract: Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel Kv1.2 (hKv1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from -80mV to 40mV. The IC50 values for the three compounds were 0.75±0.15nM, 7.6±1.2nM, and 28±4.0nM (the mean±SEM, n=3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hKv1.2. The IC50 values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild-type CHO cells were 95±7.1μM, 6.5±0.8μM (the mean±SEM, n=3), and >100μM (n=3), respectively, whereas those in the CHO cells stably expressing hKv1.2 were 78±5.8μM, 6.0±1.0μM (the mean±SEM, n=3), and >100μM (n=3). These results suggested that cytotoxicity is not triggered by inhibition of the human Kv1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose-dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells.
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan. Electronic address: konoki@m.tohoku.ac.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Konoki
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Suga
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Fuwa
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan. Electronic address: masasaki@m.tohoku.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D002922:Ciguatoxins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D035964:Oxocins
chemical_list: D002922:Ciguatoxins; D051663:Kv1.2 Potassium Channel; D011994:Recombinant Proteins; C435770:gambierol; D035964:Oxocins
keywords: Cytotoxicity; Gambierol; Voltage-gated potassium channels