title: Distinct mechanisms of block of Kv1.5 channels by tertiary and quaternary amine clofilium compounds.
abstract: The quaternary ammonium compound clofilium and its tertiary amine derivative LY97241 were used to analyze mechanisms of block in a voltage-gated potassium channel. Wild-type and mutant Kv1.5 channels expressed in Xenopus oocytes were recorded by two-electrode voltage clamp. Open-channel block to 20% of the control current amplitude was induced reversibly by 50 microM clofilium or 200 microM LY97241, and was seen as an acceleration of the macroscopic current decay. Although blockers remained present after application, channels recovered from block during each interpulse interval. The optimum voltage for recovery (-45 mV at pH 7.3) at the threshold for channel activation indicated that clofilium block and recovery occurred principally through the open channel state. In contrast, LY97241 appeared to exit from the closed state and the open state. In an acid-tolerant Kv1.5 mutant channel (H452Q), external pH was used to titrate LY97241. At low pH, which protonates the LY97241 amine group, recovery from block at hyperpolarized potentials was impaired in a manner similar to that seen with clofilium. Recovery from clofilium block was reduced at negative potentials independent of pH, an effect attributed to trapping of the permanently charged compound within the closed channels.
authors.affiliation: Department of Physiology, University of Arizona College of Medicine, Tucson Arizona 85724, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Steidl
authors.forename: A J
authors.initials: AJ
authors.lastname: Yool
mesh_terms: D000818:Animals; D005260:Female; D006863:Hydrogen-Ion Concentration; D051666:Kv1.5 Potassium Channel; D008564:Membrane Potentials / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020127:Recovery of Function / Q000502:physiology; D013997:Time Factors; D014982:Xenopus laevis
chemical_list: C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D000644:Quaternary Ammonium Compounds; C056528:LY 97241; C022799:clofilium