title: Tuning the electrical properties of the heart by differential trafficking of KATP ion channel complexes.
abstract: The copy number of membrane proteins at the cell surface is tightly regulated. Many ion channels and receptors present retrieval motifs to COPI vesicle coats and are retained in the early secretory pathway. In some cases, the interaction with COPI is prevented by binding to 14-3-3 proteins. However, the functional significance of this antagonism between COPI and 14-3-3 in terminally differentiated cells is unknown. Here, we show that ATP-sensitive K(+) (KATP) channels, which are composed of Kir6.2 and SUR1 subunits, are stalled in the Golgi complex of ventricular, but not atrial, cardiomyocytes. Upon sustained β-adrenergic stimulation, which leads to activation of protein kinase A (PKA), SUR1-containing channels reach the plasma membrane of ventricular cells. We show that PKA-dependent phosphorylation of the C-terminus of Kir6.2 decreases binding to COPI and, thereby, silences the arginine-based retrieval signal. Thus, activation of the sympathetic nervous system releases this population of KATP channels from storage in the Golgi and, hence, might facilitate the adaptive response to metabolic challenges.
authors.affiliation: Department of Molecular Biology, Center for Biochemistry and Molecular Cell Biology, Heart Research Center Göttingen, University Medicine Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Arakel
authors.forename: Sören
authors.initials: S
authors.lastname: Brandenburg
authors.forename: Keita
authors.initials: K
authors.lastname: Uchida
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhang
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Lin
authors.forename: Tobias
authors.initials: T
authors.lastname: Kohl
authors.forename: Bianca
authors.initials: B
authors.lastname: Schrul
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Sulkin
authors.forename: Igor R
authors.initials: IR
authors.lastname: Efimov
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Blanche
authors.initials: B
authors.lastname: Schwappach
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D004594:Electrophysiology; D019084:Fluorescent Antibody Technique, Indirect; D047468:Immunoprecipitation; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D064233:Sulfonylurea Receptors / Q000378:metabolism*; D000099161:Kcnj11 Channel
chemical_list: D048948:14-3-3 Proteins; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human
keywords: 14-3-3; ATP-sensitive K+ channels; Arg-based retrieval signal; COPI; Cardiomyocyte; Coatomer; KATP; PKA; Protein kinase A; Trafficking