KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging

Abstract

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 ␣ 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.cardiac dysfunction ͉ fibrillation ͉ heart ͉ long-QT syndrome ͉ longevity

Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species

“…In particular, we focused on ion channel genes that have previously been shown to regulate heart function in the adult fly (Bodmer, 2005;Akasaka et al, 2006;Ocorr et al, 2007;Qian et al, 2008a). Of these candidates, the two potassium channels dSUR and slowpoke were most severely down-regulated ( (Johnson et al, 1998;Akasaka et al, 2006).…”

“…Moreover, recent studies using multiple functional assays revealed extensive conservation of gene functions required for maintaining normal heart physiology in the adult (Bier and Bodmer, 2004;Ocorr et al, 2007;Qian et al, 2008a,b). Combined with the powerful genetic tools available in the fly, screens to identify molecular-genetic pathways involved in cardiac contractility and rhythm can now be executed, leading to the identification of novel cardiac regulators that can then be examined in mammals (Adams and Sekelsky, 2002;St Johnston, 2002;Neely et al, 2010).…”

“…Image analysis and M-mode traces on semi-intact fly preparations Procedures used were as described previously (Ocorr et al, 2007;Fink et al, 2009). In brief, flies were anesthetized and the head, ventral thorax, and fashion in the adult is limited.…”

Genetic Control of Heart Function and Aging in Drosophila

“…Mutations in a number of ion channels and transporters have been found to alter larval heart rate, including in SERCA, the Sarco-endoplasmic reticulum Ca 2+ -ATPase, and in the Ca 2+ -channel encoded by cacophony (Ray andDowse 2005,Sanyal et al 2006). Moreover, vertebrate homologs of potassium channels encoded by either-a-gogo (eag) and KCNQ are responsible for repolarization of the cardiac action potential (Kr/HERG and Ks/KCNQ; for review see Sanguinetti and Tristani-Firouzi, 2006) , and eag and KCNQ mutants in Drosophila also perturb proper heart function, further underlining the remarkable functional parallels in basic cardiac physiology between flies and humans (Johnson et al 1998;Ocorr et al 2007; for review see Bodmer et al 2005). Investigation of ion channel expression, their cardiac-specific functions and detailed contractile properties of the Drosophila heart has become more readily possible in recent years, with the advent of new experimental techniques applied to this small organism.…”

Identification of ion channel genes in the Acyrthosiphon pisum genome

“…P-element insertion lines in the KCNQ gene have shown that the KCNQ channel is involved in control of heart rhythm and the knockout line showed increased arrhythmias compared with wild-type controls (Ocorr et al, 2007). A. pisum contains a single KCNQ gene, hmm111514, which is currently modelled as a pseudogene as it contains a premature stop codon.…”