title: Mechanism of action of lolitrem B, a fungal endophyte derived toxin that inhibits BK large conductance Ca²+-activated K+ channels.
abstract: The aim of this study was to compare the mode of action of the commonly used BK inhibitor paxilline with that of the more recently discovered lolitrem B. Similarities and differences in characteristics of inhibition between the two compounds were investigated. We have previously shown that lolitrem B does not affect the BK channel G-V, in contrast to the rightward shift produced by paxilline. These different effects on the voltage-dependence of activation suggest different modes of action for these two compounds. In this study we show that inhibition by both paxilline and lolitrem B is characterized by an open state preference for BK (hSlo) channels. Both compounds had a 3-fold higher apparent affinity under conditions likely to favour the open state, suggesting they have a similar BK conformational preference for binding. Furthermore, both compounds had a calcium concentration-dependence to their inhibitory effects. The G-V shift induced by paxilline was calcium concentration-dependent.
authors.affiliation: AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston North 4442, New Zealand.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Imlach
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Finch
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang
authors.forename: James
authors.initials: J
authors.lastname: Dunlop
authors.forename: Julie E
authors.initials: JE
authors.lastname: Dalziel
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D009183:Mycotoxins / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D026121:Indole Alkaloids; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009183:Mycotoxins; C048220:paxilline; C033673:lolitrem B; D002118:Calcium