title: Cardiac-specific ablation of synapse-associated protein SAP97 in mice decreases potassium currents but not sodium current.
abstract: BACKGROUND
  Membrane-associated guanylate kinase (MAGUK) proteins are important determinants of ion channel organization in the plasma membrane. In the heart, the MAGUK protein SAP97, encoded by the DLG1 gene, interacts with several ion channels via their PDZ domain-binding motif and regulates their function and localization.
  
  
  OBJECTIVE
  The purpose of this study was to assess in vivo the role of SAP97 in the heart by generating a genetically modified mouse model in which SAP97 is suppressed exclusively in cardiomyocytes.
  
  
  METHODS
  SAP97(fl/fl) mice were generated by inserting loxP sequences flanking exons 1-3 of the SAP97 gene. SAP97(fl/fl) mice were crossed with αMHC-Cre mice to generate αMHC-Cre/SAP97(fl/fl) mice, thus resulting in a cardiomyocyte-specific deletion of SAP97. Quantitative reverse transcriptase-polymerase chain reaction, western blots, and immunostaining were performed to measure mRNA and protein expression levels, and ion channel localization. The patch-clamp technique was used to record ion currents and action potentials. Echocardiography and surface ECGs were performed on anesthetized mice.
  
  
  RESULTS
  Action potential duration was greatly prolonged in αMHC-Cre/SAP97(fl/fl) cardiomyocytes compared to SAP97(fl/fl) controls, but maximal upstroke velocity was unchanged. This was consistent with the decreases observed in IK1, Ito, and IKur potassium currents and the absence of effect on the sodium current INa. Surface ECG revealed an increased corrected QT interval in αMHC-Cre/SAP97(fl/fl) mice.
  
  
  CONCLUSIONS
  These data suggest that ablation of SAP97 in the mouse heart mainly alters potassium channel function. Based on the important role of SAP97 in regulating the QT interval, DLG1 may be a susceptibility gene to be investigated in patients with congenital long QT syndrome.
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland. Electronic address: ludovic.gillet@dkf.unibe.ch.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Gillet
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Rougier
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Shy
authors.affiliation: PolyGene AG, Rümlang, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Sonntag
authors.affiliation: Plateau d'Expérimentation Coeur, Muscle, Vaisseaux, Université Pierre et Marie Curie, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Essers
authors.affiliation: PolyGene AG, Rümlang, Switzerland.
authors.forename: Doron
authors.initials: D
authors.lastname: Shmerling
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S1166, Institut de Recherche Sur Les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France; Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Balse
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S1166, Institut de Recherche Sur Les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France; Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Stéphane N
authors.initials: SN
authors.lastname: Hatem
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland. Electronic address: hugues.abriel@dkf.unibe.ch.
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D000074288:Discs Large Homolog 1 Protein; D004195:Disease Models, Animal; D004562:Electrocardiography; D051528:Guanylate Kinases / Q000502:physiology*; D008133:Long QT Syndrome / Q000209:etiology* / Q000503:physiopathology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D061566:Voltage-Gated Sodium Channels / Q000502:physiology*
chemical_list: D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; D024642:Potassium Channels, Voltage-Gated; D061566:Voltage-Gated Sodium Channels; D051528:Guanylate Kinases
keywords: Action potential; Potassium channel; SAP97; Sodium channel; Tissue-specific knockout