{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T22:18:27Z","timestamp":1770675507180,"version":"3.49.0"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disturbance of the heart rhythm (arrhythmia) that is induced by stress or that occurs during exercise. Most mutations that have been linked to CPVT are found in two genes, i.e., ryanodine receptor 2 (RyR2) and calsequestrin 2 (CASQ2), two proteins fundamentally involved in the regulation of intracellular Ca<jats:sup>2+<\/jats:sup> in cardiac myocytes. We inserted six CPVT-causing mutations <jats:italic>via<\/jats:italic> clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 into <jats:italic>unc-68<\/jats:italic> and <jats:italic>csq-1<\/jats:italic>, the <jats:italic>Caenorhabditis elegans<\/jats:italic> homologs of RyR and CASQ, respectively. We characterized those mutations <jats:italic>via<\/jats:italic> video-microscopy, electrophysiology, and calcium imaging in our previously established optogenetic arrhythmia model. In this study, we additionally enabled high(er) throughput recordings of intact animals by combining optogenetic stimulation with a microfluidic chip system. Whereas only minor\/no pump deficiency of the pharynx was observed at baseline, three mutations of UNC-68 (S2378L, P2460S, Q4623R; RyR2-S2246L, -P2328S, -Q4201R) reduced the ability of the organ to follow 4 Hz optogenetic stimulation. One mutation (Q4623R) was accompanied by a strong reduction of maximal pump rate. In addition, S2378L and Q4623R evoked an altered calcium handling during optogenetic stimulation. The 1,4-benzothiazepine S107, which is suggested to stabilize RyR2 channels by enhancing the binding of calstabin2, reversed the reduction of pumping ability in a mutation-specific fashion. However, this depends on the presence of FKB-2, a <jats:italic>C. elegans<\/jats:italic> calstabin2 homolog, indicating the involvement of calstabin2 in the disease-causing mechanisms of the respective mutations. In conclusion, we showed for three CPVT-like mutations in <jats:italic>C. elegans<\/jats:italic> RyR a reduced pumping ability upon light stimulation, i.e., an arrhythmia-like phenotype, that can be reversed in two cases by the benzothiazepine S107 and that depends on stabilization <jats:italic>via<\/jats:italic> FKB-2. The genetically amenable nematode in combination with optogenetics and high(er) throughput recordings is a promising straightforward system for the investigation of RyR mutations and the selection of mutation-specific drugs.<\/jats:p>","DOI":"10.3389\/fphys.2022.691829","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T18:49:43Z","timestamp":1648579783000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["An Optogenetic Arrhythmia Model\u2014Insertion of Several Catecholaminergic Polymorphic Ventricular Tachycardia Mutations Into Caenorhabditis elegans UNC-68 Disturbs Calstabin-Mediated Stabilization of the Ryanodine Receptor Homolog"],"prefix":"10.3389","volume":"13","author":[{"given":"Marcial Alexander","family":"Engel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves Ren\u00e9","family":"W\u00f6rmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Kaestner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Sch\u00fcler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2013.00002","article-title":"Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics.","volume":"6","author":"Akerboom","year":"2013","journal-title":"Front. 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