title: Direct block of cloned hKv1.5 channel by cytochalasins, actin-disrupting agents.
abstract: The action of cytochalasins, actin-disrupting agents on human Kv1.5 channel (hKv1.5) stably expressed in Ltk(-) cells was investigated using the whole cell patch-clamp technique. Cytochalasin B inhibited hKv1.5 currents rapidly and reversibly at +60 mV in a concentration-dependent manner with an IC(50) of 4.2 microM. Cytochalasin A, which has a structure very similar to cytochalasin B, inhibited hKv1.5 (IC(50) of 1.4 microM at +60 mV). Pretreatment with other actin filament disruptors cytochalasin D and cytochalasin J, and an actin filament stabilizing agent phalloidin had no effect on the cytochalasin B-induced inhibition of hKv1.5 currents. Cytochalasin B accelerated the decay rate of inactivation for the hKv1.5 currents. Cytochalasin B-induced inhibition of the hKv1.5 channels was voltage dependent with a steep increase over the voltage range of the channel's opening. However, the inhibition exhibited voltage independence over the voltage range in which channels are fully activated. Cytochalasin B produced no significant effect on the steady-state activation or inactivation curves. The rate constants for association and dissociation of cytochalasin B were 3.7 microM/s and 7.5 s(-1), respectively. Cytochalasin B produced a use-dependent inhibition of hKv1.5 current that was consistent with the slow recovery from inactivation in the presence of the drug. Cytochalasin B (10 microM) also inhibited an ultrarapid delayed rectifier K(+) current (I(K,ur)) in human atrial myocytes. These results indicate that cytochalasin B primarily blocks activated hKv1.5 channels and endogenous I(K,ur) in a cytoskeleton-independent manner as an open-channel blocker.
authors.affiliation: Department of Pharmacology, Chonbuk National University Medical School, Chonju, Chonbuk 561-180, Republic of Korea.
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Choi
authors.forename: Jung-Ah
authors.initials: JA
authors.lastname: Park
authors.forename: Kyung-Ryoul
authors.initials: KR
authors.lastname: Kim
authors.forename: Ggot-Im
authors.initials: GI
authors.lastname: Lee
authors.forename: Yong-Tae
authors.initials: YT
authors.lastname: Lee
authors.forename: Huhn
authors.initials: H
authors.lastname: Choe
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Ko
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Kim
authors.forename: Yeon-Ho
authors.initials: YH
authors.lastname: Seo
authors.forename: Yong-Geun
authors.initials: YG
authors.lastname: Kwak
mesh_terms: D000199:Actins / Q000187:drug effects*; D000818:Animals; D003572:Cytochalasins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051666:Kv1.5 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000199:Actins; D003572:Cytochalasins; C496981:KCNA5 protein, human; C496982:Kcna5 protein, mouse; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated