%0 Journal Article %1 Temp_2005_62 %A Temple, Joel %A Frias, Patricio %A Rottman, Jeffrey %A Yang, Tao %A Wu, Yuejin %A Verheijck, E. Etienne %A Zhang, Wei %A Siprachanh, Chanthaphaychith %A Kanki, Hideaki %A Atkinson, James B %A King, Paul %A Anderson, Mark E %A Kupershmidt, Sabina %A Roden, Dan M %D 2005 %J Circ. Res. %K AMP-Dependent Action Adjuvant, Adolescent, Adul, Aged, Aldehydes, Alveolar Animals, Antineoplastic Arrhythmia, Atrial Biological, C57BL, Calcium Calcium, Cardiomyopathies, Cell Channel, Channels, Chemotherapy Chemotherapy, Cohort Combined Congestive, Cyclic Cyclophosphamide, Dacarbazine, Dependent Diagnosis, Differential, Disease Disease, Diseases, Doxorubicin, Extramural, Failure, Female, Fibrillation, Flecainide, Gastrointestinal Genetic Genetic, Gov't, Heart Heart, Hematoma, Hemorrhage, Homeostasis, Humans, Ifosfamide, Inbred Infarction, Isoprostanes, Isoproterenol, Kinase, Kinases, Knockout, L-Type, Line, Lipid Long Male, Mesna, Metastasis, Mice, Missense, Models, Mutation, Myocardial Myocardium, N.I.H., Neoplasm Non-U.S. Oxidative P.H.S., Part, Peroxidation, Polymorphism, Potassium Potentials, Predisposition Protein Protocols, QT Receptor Rectal Release Research Ryanodine Sarcoma, Screening, Soft Staging, Stress, Studies, Support, Susceptibility, Syndrome, to {C}a$^{2+}$-Calmodulin %N 1 %P 62--69 %R 10.1161/01.RES.0000173047.42236.88 %T Atrial fibrillation in KCNE1-null mice. %U http://dx.doi.org/10.1161/01.RES.0000173047.42236.88 %V 97 %X 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.

@article{Temp_2005_62, 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.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Temple, Joel and Frias, Patricio and Rottman, Jeffrey and Yang, Tao and Wu, Yuejin and Verheijck, E. Etienne and Zhang, Wei and Siprachanh, Chanthaphaychith and Kanki, Hideaki and Atkinson, James B and King, Paul and Anderson, Mark E and Kupershmidt, Sabina and Roden, Dan M}, biburl = {https://www.bibsonomy.org/bibtex/284eba1a996df591e805b5d2512ba043d/hake}, description = {The whole bibliography file I use.}, doi = {10.1161/01.RES.0000173047.42236.88}, file = {Temp_2005_62.pdf:Temp_2005_62.pdf:PDF}, interhash = {971ac29e94cfb383798e89f340bcfe08}, intrahash = {84eba1a996df591e805b5d2512ba043d}, journal = {Circ. Res.}, key = 284, keywords = {AMP-Dependent Action Adjuvant, Adolescent, Adul, Aged, Aldehydes, Alveolar Animals, Antineoplastic Arrhythmia, Atrial Biological, C57BL, Calcium Calcium, Cardiomyopathies, Cell Channel, Channels, Chemotherapy Chemotherapy, Cohort Combined Congestive, Cyclic Cyclophosphamide, Dacarbazine, Dependent Diagnosis, Differential, Disease Disease, Diseases, Doxorubicin, Extramural, Failure, Female, Fibrillation, Flecainide, Gastrointestinal Genetic Genetic, Gov't, Heart Heart, Hematoma, Hemorrhage, Homeostasis, Humans, Ifosfamide, Inbred Infarction, Isoprostanes, Isoproterenol, Kinase, Kinases, Knockout, L-Type, Line, Lipid Long Male, Mesna, Metastasis, Mice, Missense, Models, Mutation, Myocardial Myocardium, N.I.H., Neoplasm Non-U.S. Oxidative P.H.S., Part, Peroxidation, Polymorphism, Potassium Potentials, Predisposition Protein Protocols, QT Receptor Rectal Release Research Ryanodine Sarcoma, Screening, Soft Staging, Stress, Studies, Support, Susceptibility, Syndrome, to {C}a$^{2+}$-Calmodulin}, month = Jul, number = 1, pages = {62--69}, pii = {01.RES.0000173047.42236.88}, pmid = {15947250}, timestamp = {2009-06-03T11:21:34.000+0200}, title = {Atrial fibrillation in KCNE1-null mice.}, url = {http://dx.doi.org/10.1161/01.RES.0000173047.42236.88}, volume = 97, year = 2005 }