1. Selective regulation of human TRAAK channels by biologically active phospholipids
- Author
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Arthur Laganowsky, David H. Russell, Minglei Zhao, Jacob W. McCabe, Mariah Bartz, Samantha Schrecke, Charles Packianathan, Yun Zhu, and Ming Zhou
- Subjects
Adenosine ,Potassium Channels ,Genetic Vectors ,Gene Expression ,Phosphatidic Acids ,Glycerophospholipids ,Phosphatidylserines ,Plasma protein binding ,Pichia ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Humans ,Protein Isoforms ,Cloning, Molecular ,Molecular Biology ,Ion channel ,Ion transporter ,030304 developmental biology ,chemistry.chemical_classification ,Membrane potential ,0303 health sciences ,Liposome ,Ion Transport ,Phosphatidylethanolamines ,030302 biochemistry & molecular biology ,Fatty acid ,Phosphatidylglycerols ,Cell Biology ,Phosphatidic acid ,Cations, Monovalent ,Recombinant Proteins ,Dissociation constant ,Kinetics ,chemistry ,Liposomes ,Phosphatidylcholines ,Potassium ,Biophysics ,Ion Channel Gating ,Protein Binding - Abstract
TRAAK is an ion channel from the two-pore domain potassium (K2P) channel family with roles in maintaining the resting membrane potential and fast action potential conduction. Regulated by a wide range of physical and chemical stimuli, the affinity and selectivity of K2P4.1 towards lipids remains poorly understood. Here we show the two isoforms of K2P4.1 have distinct binding preferences for lipids dependent on acyl chain length and position on the glycerol backbone. Unexpectedly, the channel can also discriminate the fatty acid linkage at the sn-1 position. Of the 33 lipids interrogated using native mass spectrometry, phosphatidic acid (PA) had the lowest equilibrium dissociation constants for both isoforms of K2P4.1. Liposome potassium flux assays with K2P4.1 reconstituted in defined lipid environments show that those containing PA activate the channel in a dose-dependent fashion. Our results begin to define the molecular requirements for the specific binding of lipids to K2P4.1.
- Published
- 2020
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