KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging.
Population profiles of industrialized countries show dramatic increases in cardiovascular disease with age, but the molecular and genetic basis of disease progression has been difficult to study because of the lack of suitable model systems. Our studies of Drosophila show a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in the expression of the Drosophila homolog of human KCNQ1-encoded K(+) channel alpha subunits. In humans, this channel is involved in myocardial repolarization, and alterations in the function of this channel are associated with an increased risk for Torsades des Pointes arrhythmias and sudden death. Hearts from young KCNQ1 mutant fruit flies exhibit prolonged contractions and fibrillations reminiscent of Torsades des Pointes arrhythmias, and they exhibit severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in WT flies. The fibrillations observed in mutant flies correlate with delayed relaxation of the myocardium, as revealed by increases in the duration of phasic contractions, extracellular field potentials, and in the baseline diastolic tension. These results suggest that K(+) currents, mediated by a KCNQ channel, contribute to the repolarization reserve of fly hearts, ensuring normal excitation-contraction coupling and rhythmical contraction. That arrhythmias in both WT and KCNQ1 mutants become worse as flies age suggests that additional factors are also involved.
Ocorr
Karen
K
Center for Neuroscience and Aging, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Reeves
Nick L
NL
Wessells
Robert J
RJ
Fink
Martin
M
Chen
H-S Vincent
HS
Akasaka
Takeshi
T
Yasuda
Soichiro
S
Metzger
Joseph M
JM
Giles
Wayne
W
Posakony
James W
JW
Bodmer
Rolf
R
D000375:Aging; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D004331:Drosophila melanogaster; D004594:Electrophysiology; D005786:Gene Expression Regulation; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D013997:Time Factors; D016171:Torsades de Pointes / Q000235:genetics
D051656:KCNQ Potassium Channels