title: Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in the United States alone. Despite decades of research, surprisingly little is known regarding the molecular pathways underlying the pathogenesis of AF. ANK2 encodes ankyrin-B, a multifunctional adapter molecule implicated in membrane targeting of ion channels, transporters, and signaling molecules in excitable cells.
  
  
  RESULTS
  In the present study, we report early-onset AF in patients harboring loss-of-function mutations in ANK2. In mice, we show that ankyrin-B deficiency results in atrial electrophysiological dysfunction and increased susceptibility to AF. Moreover, ankyrin-B(+/-) atrial myocytes display shortened action potentials, consistent with human AF. Ankyrin-B is expressed in atrial myocytes, and we demonstrate its requirement for the membrane targeting and function of a subgroup of voltage-gated Ca(2+) channels (Ca(v)1.3) responsible for low voltage-activated L-type Ca(2+) current. Ankyrin-B is associated directly with Ca(v)1.3, and this interaction is regulated by a short, highly conserved motif specific to Ca(v)1.3. Moreover, loss of ankyrin-B in atrial myocytes results in decreased Ca(v)1.3 expression, membrane localization, and function sufficient to produce shortened atrial action potentials and arrhythmias. Finally, we demonstrate reduced ankyrin-B expression in atrial samples of patients with documented AF, further supporting an association between ankyrin-B and AF.
  
  
  CONCLUSIONS
  These findings support that reduced ankyrin-B expression or mutations in ANK2 are associated with AF. Additionally, our data demonstrate a novel pathway for ankyrin-B-dependent regulation of Ca(v)1.3 channel membrane targeting and regulation in atrial myocytes.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, 43210, USA.
authors.forename: Shane R
authors.initials: SR
authors.lastname: Cunha
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Seyed
authors.initials: S
authors.lastname: Hashemi
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Patrick
authors.initials: P
authors.lastname: Wright
authors.forename: Olha
authors.initials: O
authors.lastname: Koval
authors.forename: Jingdong
authors.initials: J
authors.lastname: Li
authors.forename: Hjalti
authors.initials: H
authors.lastname: Gudmundsson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gumina
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Herve
authors.initials: H
authors.lastname: Le Marec
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D017487:Ankyrins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency* / Q000235:genetics; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins; D015220:Calcium Channels; C093712:Cacna1d protein, rat