PT - JOURNAL ARTICLE AU - Luisa L Scott AU - Sangeetha Iyer AU - Ashley E. Philpo AU - Melva N. Avalos AU - Natalie S. Wu AU - Ted Shi AU - Brooke A. Prakash AU - Thanh-Tu Nguyen AU - S. John Mihic AU - Richard W. Aldrich AU - Jonathan T. Pierce TI - A novel peptide restricts ethanol modulation of the BK channel <em>in vitro</em> and <em>in vivo</em> AID - 10.1124/jpet.118.251918 DP - 2018 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.118.251918 4099 - http://jpet.aspetjournals.org/content/early/2018/08/29/jpet.118.251918.short 4100 - http://jpet.aspetjournals.org/content/early/2018/08/29/jpet.118.251918.full AB - Alcohol is a widely used and abused substance. A major unresolved issue in the alcohol research field is determining which of the many alcohol target proteins identified to date is responsible for shaping each specific alcohol-related behavior. The large-conductance, calcium- and voltage-activated potassium channel, or BK channel, is a conserved target of ethanol. Genetic manipulation of the highly conserved BKα channel influences alcohol-related behaviors across phylogenetically diverse species that include worm, fly, mouse, and man. A pharmacological tool that prevents alcohol's action at a single target, like the BK channel, would complement genetic approaches in the quest to define the behavioral consequences of alcohol at each target. To identify agents that specifically modulate the action of ethanol at the BK channel, we executed a high-throughput phagemid-display screen in combination with a C. elegans behavioral genetics assay. This screen selected a novel nonapeptide, LS10, that moderated acute ethanol intoxication in a BK channel-humanized C. elegans strain without altering basal behavior. LS10's action in vivo was dependent upon BK channel functional activity. Single-channel electrophysiological recordings in vitro showed that pre-incubation with a sub-micromolar concentration of LS10 restricted ethanol-induced changes in human BKα channel gating. In contrast, no substantial changes in basal human BKα channel function were observed after LS10 application. The LS10 peptide provides a proof of concept that a combined phagemid-display/behavioral genetics screening approach can provide novel tools for understanding the action of alcohol at the BK channel and how this, in turn, exerts influence over CNS function.