title: Arrhythmogenic effects of mutated L-type Ca 2+-channels on an optogenetically paced muscular pump in Caenorhabditis elegans.
abstract: Cardiac arrhythmias are often associated with mutations in ion channels or other proteins. To enable drug development for distinct arrhythmias, model systems are required that allow implementing patient-specific mutations. We assessed a muscular pump in Caenorhabditis elegans. The pharynx utilizes homologues of most of the ion channels, pumps and transporters defining human cardiac physiology. To yield precise rhythmicity, we optically paced the pharynx using channelrhodopsin-2. We assessed pharynx pumping by extracellular recordings (electropharyngeograms--EPGs), and by a novel video-microscopy based method we developed, which allows analyzing multiple animals simultaneously. Mutations in the L-type VGCC (voltage-gated Ca(2+)-channel) EGL-19 caused prolonged pump duration, as found for analogous mutations in the Cav1.2 channel, associated with long QT syndrome. egl-19 mutations affected ability to pump at high frequency and induced arrhythmicity. The pharyngeal neurons did not influence these effects. We tested whether drugs could ameliorate arrhythmia in the optogenetically paced pharynx. The dihydropyridine analog Nemadipine A prolonged pump duration in wild type, and reduced or prolonged pump duration of distinct egl-19 alleles, thus indicating allele-specific effects. In sum, our model may allow screening of drug candidates affecting specific VGCCs mutations, and permit to better understand the effects of distinct mutations on a macroscopic level.
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.|Institute of Biochemistry, Goethe University, Max von Laue Strasse 9, D-60438 Frankfurt, Germany.|Cluster of Excellence Frankfurt-Macromolecular Complexes, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schüler
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.|Institute of Biochemistry, Goethe University, Max von Laue Strasse 9, D-60438 Frankfurt, Germany.|Cluster of Excellence Frankfurt-Macromolecular Complexes, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Fischer
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.|Institute of Biochemistry, Goethe University, Max von Laue Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Lior
authors.initials: L
authors.lastname: Shaltiel
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.|Institute of Biochemistry, Goethe University, Max von Laue Strasse 9, D-60438 Frankfurt, Germany.
authors.forename: Wagner
authors.initials: W
authors.lastname: Steuer Costa
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.|Institute of Biochemistry, Goethe University, Max von Laue Strasse 9, D-60438 Frankfurt, Germany.|Cluster of Excellence Frankfurt-Macromolecular Complexes, Goethe University, Max von Laue Strasse 15, D-60438 Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gottschalk
mesh_terms: D000483:Alleles; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D015870:Gene Expression; D007734:Kymography; D008027:Light; D018715:Microscopy, Video; D009119:Muscle Contraction / Q000235:genetics / Q000528:radiation effects; D009154:Mutation; D062308:Optogenetics; D010609:Pharyngeal Muscles / Q000166:cytology / Q000502:physiology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D012243:Rhodopsin