title: Atomic determinants of BK channel activation by polyunsaturated fatty acids.
abstract: Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca2+- and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104; hoshi@hoshi.org yttian1983@gmail.com.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Marius
authors.initials: M
authors.lastname: Aursnes
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Trond Vidar
authors.initials: TV
authors.lastname: Hansen
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Jørn Eivind
authors.initials: JE
authors.lastname: Tungen
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Galpin
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors.forename: Lilia
authors.initials: L
authors.lastname: Leisle
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ahern
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, D-07745 Jena, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104; hoshi@hoshi.org yttian1983@gmail.com.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
mesh_terms: D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D015525:Fatty Acids, Omega-3 / Q000737:chemistry* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D005395:Fish Oils / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000737:chemistry / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry / Q000378:metabolism
chemical_list: D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D005395:Fish Oils; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D004281:Docosahexaenoic Acids
keywords: chemical biology; docosahexaenoic acid; fish oil; ion–dipole; unnatural amino acids