Arrhythmogenic effects of mutated L-Type Ca 2+ -channels on an optogenetically paced muscular pump in Caenorhabditis elegans

Christina Schüler, Elisabeth Fischer, Lior Shaltiel, Wagner Steuer Costa, Alexander Gottschalk*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 Ca v 1.2 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.

Original languageAmerican English
Article number14427
JournalScientific Reports
Volume5
DOIs
StatePublished - 24 Sep 2015
Externally publishedYes

Fingerprint

Dive into the research topics of 'Arrhythmogenic effects of mutated L-Type Ca 2+ -channels on an optogenetically paced muscular pump in Caenorhabditis elegans'. Together they form a unique fingerprint.

Cite this