title: Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts.
abstract: BACKGROUND
  Fibroblast growth factor homologous factors (FHFs), a subfamily of fibroblast growth factors (FGFs) that are incapable of functioning as growth factors, are intracellular modulators of Na(+) channels and have been linked to neurodegenerative diseases. Although certain FHFs have been found in embryonic heart, they have not been reported in adult heart, and they have not been shown to regulate endogenous cardiac Na(+) channels or to participate in cardiac pathophysiology.
  
  
  OBJECTIVE
  We tested whether FHFs regulate Na(+) channels in murine heart.
  
  
  RESULTS
  We demonstrated that isoforms of FGF13 are the predominant FHFs in adult mouse ventricular myocytes. FGF13 binds directly to, and colocalizes with, the Na(V)1.5 Na(+) channel in the sarcolemma of adult mouse ventricular myocytes. Knockdown of FGF13 in adult mouse ventricular myocytes revealed a loss of function of Na(V)1.5-reduced Na(+) current density, decreased Na(+) channel availability, and slowed Na(V)1.5-reduced Na(+) current recovery from inactivation. Cell surface biotinylation experiments showed ≈45% reduction in Na(V)1.5 protein at the sarcolemma after FGF13 knockdown, whereas no changes in whole-cell Na(V)1.5 protein or in mRNA level were observed. Optical imaging in neonatal rat ventricular myocyte monolayers demonstrated slowed conduction velocity and a reduced maximum capture rate after FGF13 knockdown.
  
  
  CONCLUSIONS
  These findings show that FHFs are potent regulators of Na(+) channels in adult ventricular myocytes and suggest that loss-of-function mutations in FHFs may underlie a similar set of cardiac arrhythmias and cardiomyopathies that result from Na(V)1.5 loss-of-function mutations.
authors.affiliation: Departments of Medicine/Cardiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hennessey
authors.forename: Robert D
authors.initials: RD
authors.lastname: Kirkton
authors.forename: Chaojian
authors.initials: C
authors.lastname: Wang
authors.forename: Victoria
authors.initials: V
authors.lastname: Graham
authors.forename: Ram S
authors.initials: RS
authors.lastname: Puranam
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rosenberg
authors.forename: Nenad
authors.initials: N
authors.lastname: Bursac
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D019921:Biotinylation; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism*; D015640:Ion Channel Gating; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors; D012964:Sodium