Atomic determinants of BK channel activation by polyunsaturated fatty acids

Yutao Tian; Marius Aursnes; Trond Vidar Hansen; Jørn Eivind Tungen; Jason D Galpin; Lilia Leisle; Christopher A Ahern; Rong Xu; Stefan H Heinemann; Toshinori Hoshi

doi:10.1073/pnas.1615562113

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Atomic determinants of BK channel activation by polyunsaturated fatty acids

Journal article

Open access

Peer reviewed

Atomic determinants of BK channel activation by polyunsaturated fatty acids

Yutao Tian, Marius Aursnes, Trond Vidar Hansen, Jørn Eivind Tungen, Jason D Galpin, Lilia Leisle, Christopher A Ahern, Rong Xu, Stefan H Heinemann and Toshinori Hoshi

Proceedings of the National Academy of Sciences - PNAS, Vol.113(48), pp.13905-13910

11/29/2016

DOI: 10.1073/pnas.1615562113

PMCID: PMC5137720

PMID: 27849612

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Abstract

Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca - 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.

Docosahexaenoic Acids - therapeutic use

Large-Conductance Calcium-Activated Potassium Channels - metabolism

Fatty Acids, Omega-3 - metabolism

Docosahexaenoic Acids - chemistry

Humans

Fatty Acids, Omega-3 - chemistry

Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - chemistry

Fatty Acids, Unsaturated - therapeutic use

Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - metabolism

Fatty Acids, Unsaturated - metabolism

Large-Conductance Calcium-Activated Potassium Channels - chemistry

Ion Channel Gating - genetics

Fatty Acids, Unsaturated - chemistry

Fish Oils - metabolism

Fish Oils - chemistry

Docosahexaenoic Acids - metabolism

Details

Title: Subtitle: Atomic determinants of BK channel activation by polyunsaturated fatty acids
Creators: Yutao Tian - Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104; hoshi@hoshi.org yttian1983@gmail.com
Marius Aursnes - Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway
Trond Vidar Hansen - Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway
Jørn Eivind Tungen - Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway
Jason D Galpin - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Lilia Leisle - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Christopher A Ahern - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Rong Xu - Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104
Stefan H Heinemann - Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, D-07745 Jena, Germany
Toshinori Hoshi - Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104; hoshi@hoshi.org yttian1983@gmail.com
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.113(48), pp.13905-13910
DOI: 10.1073/pnas.1615562113
PMID: 27849612
PMCID: PMC5137720
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: U54 GM087519 / NIGMS NIH HHS R01 GM106569 / NIGMS NIH HHS R01 GM057654 / NIGMS NIH HHS
Language: English
Date published: 11/29/2016
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984070877902771

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