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Atrial fibrillation in KCNE1-null mice.

Abstract
Although atrial fibrillation is the most common serious cardiac arrhythmia, the fundamental molecular pathways remain undefined. Mutations in KCNQ1, one component of a sympathetically activated cardiac potassium channel complex, cause familial atrial fibrillation, although the mechanisms in vivo are unknown. We show here that mice with deletion of the KCNQ1 protein partner KCNE1 have spontaneous episodes of atrial fibrillation despite normal atrial size and structure. Isoproterenol abolishes these abnormalities, but vagomimetic interventions have no effect. Whereas loss of KCNE1 function prolongs ventricular action potentials in humans, KCNE1-/- mice displayed unexpectedly shortened atrial action potentials, and multiple potential mechanisms were identified: (1) K+ currents (total and those sensitive to the KCNQ1 blocker chromanol 293B) were significantly increased in atrial cells from KCNE1-/- mice compared with controls, and (2) when CHO cells expressing KCNQ1 and KCNE1 were pulsed very rapidly (at rates comparable to the normal mouse heart and to human atrial fibrillation), the sigmoidicity of IKs activation prevented current accumulation, whereas cells expressing KCNQ1 alone displayed marked current accumulation at these very rapid rates. Thus, KCNE1 deletion in mice unexpectedly leads to increased outward current in atrial myocytes, shortens atrial action potentials, and enhances susceptibility to atrial fibrillation.
AuthorsJoel Temple, Patricio Frias, Jeffrey Rottman, Tao Yang, Yuejin Wu, E Etienne Verheijck, Wei Zhang, Chanthaphaychith Siprachanh, Hideaki Kanki, James B Atkinson, Paul King, Mark E Anderson, Sabina Kupershmidt, Dan M Roden
JournalCirculation research (Circ Res) Vol. 97 Issue 1 Pg. 62-9 (Jul 08 2005) ISSN: 1524-4571 [Electronic] United States
PMID15947250 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Kcne1 protein, mouse
  • Potassium Channels, Voltage-Gated
  • Isoproterenol
Topics
  • Action Potentials
  • Animals
  • Atrial Fibrillation (etiology, physiopathology)
  • Disease Susceptibility
  • Isoproterenol (pharmacology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Potassium Channels, Voltage-Gated (genetics, physiology)

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