title: Marine n-3 PUFAs modulate IKs gating, channel expression, and location in membrane microdomains.
abstract: OBJECTIVE
  Polyunsaturated fatty n-3 acids (PUFAs) have been reported to exhibit antiarrhythmic properties. However, the mechanisms of action remain unclear. We studied the electrophysiological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on IKs, and on the expression and location of Kv7.1 and KCNE1.
  
  
  RESULTS
  Experiments were performed using patch-clamp, western blot, and sucrose gradient techniques in COS7 cells transfected with Kv7.1/KCNE1 channels. Acute perfusion with both PUFAs increased Kv7.1/KCNE1 current, this effect being greater for DHA than for EPA. Similar results were found in guinea pig cardiomyocytes. Acute perfusion of either PUFA slowed the activation kinetics and EPA shifted the activation curve to the left. Conversely, chronic EPA did not modify Kv7.1/KCNE1 current magnitude and shifted the activation curve to the right. Chronic PUFAs decreased the expression of Kv7.1, but not of KCNE1, and induced spatial redistribution of Kv7.1 over the cell membrane. Cholesterol depletion with methyl-β-cyclodextrin increased Kv7.1/KCNE1 current magnitude. Under these conditions, acute EPA produced similar effects than those induced in non-cholesterol-depleted cells. A ventricular action potential computational model suggested antiarrhythmic efficacy of acute PUFA application under IKr block.
  
  
  CONCLUSIONS
  We provide evidence that acute application of PUFAs increases Kv7.1/KCNE1 through a probably direct effect, and shows antiarrhythmic efficacy under IKr block. Conversely, chronic EPA application modifies the channel activity through a change in the Kv7.1/KCNE1 voltage-dependence, correlated with a redistribution of Kv7.1 over the cell membrane. This loss of function may be pro-arrhythmic. This shed light on the controversial effects of PUFAs regarding arrhythmias.
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, C/Arturo Duperier 4, 28029 Madrid, Spain cvalenzuela@iib.uam.es c.moreno@maastrichtuniversity.nl.
authors.forename: Cristina
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, C/Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: de la Cruz
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Oliveras
authors.affiliation: Biomedical Engineering Laboratory D.E.I.S., University of Bologna, 47521 Cesena, Italy.
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Kharche
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, C/Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Guizy
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Nùria
authors.initials: N
authors.lastname: Comes
authors.affiliation: Biomedical Engineering Laboratory D.E.I.S., University of Bologna, 47521 Cesena, Italy.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Starý
authors.affiliation: Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Ronchi
authors.affiliation: Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.affiliation: L'Institut du Thorax, Unité Inserm UMR 1087/CNRS UMR 6291, Nantes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baró
authors.affiliation: L'Institut du Thorax, Unité Inserm UMR 1087/CNRS UMR 6291, Nantes, France.
authors.forename: Gildas
authors.initials: G
authors.lastname: Loussouarn
authors.affiliation: Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
authors.affiliation: Biomedical Engineering Laboratory D.E.I.S., University of Bologna, 47521 Cesena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Severi
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Felipe
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, C/Arturo Duperier 4, 28029 Madrid, Spain cvalenzuela@iib.uam.es c.moreno@maastrichtuniversity.nl.
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D021962:Membrane Microdomains / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D005231:Fatty Acids, Unsaturated; C502068:KCNE5 protein, human; D024642:Potassium Channels, Voltage-Gated; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid
keywords: DHA; EPA; IKs; KCNE1; Kv7.1; Lipid rafts; PUFAs