{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:21:37Z","timestamp":1787008897651,"version":"build-2736575974"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R250-2017-134"],"award-info":[{"award-number":["R250-2017-134"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R324-2019-1933"],"award-info":[{"award-number":["R324-2019-1933"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R324-2019-2035"],"award-info":[{"award-number":["R324-2019-2035"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002808","name":"Carlsberg Foundation","doi-asserted-by":"publisher","award":["CF19-0668"],"award-info":[{"award-number":["CF19-0668"]}],"id":[{"id":"10.13039\/501100002808","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Obelske Familiefond"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In humans, mutations in calmodulin cause cardiac arrhythmia. These mutations disrupt the ability of calmodulin to sense calcium concentrations and correctly regulate two central calcium channels, together obstructing heart rhythm. This correlation is well established, but also surprising since calmodulin is expressed in all tissues and interacts with hundreds of proteins. Until now, most studies have focused on cardiac cell function and regulation of specific cardiac targets, and thus, potential other effects of these mutations have largely been unexplored. Here, we introduce the nematode Caenorhabditis elegans as an in vivo model to study effects of three human calmodulin mutations with different impairment on calcium binding. We find that arrhythmic effects of the calmodulin mutations N54I and D96V can be recapitulated in disruption of two rhythmic behaviors, pharynx pumping and defecation motor program. Interestingly, we also find that these mutations affect neuronal function, but in different ways. Whereas D96V sensitizes signaling at the neuromuscular junction, N54I has a protective effect. The mutation N98S did not affect rhythmic behavior, but impaired chemosensing. Therefore, pathogenic calmodulin mutations act through different mechanisms in rhythmic behavior and neuronal function in C. elegans, emphasizing the strength of using live multicellular models. Finally, our results support the hypothesis that human calmodulin mutations could also contribute to neurological diseases.<\/jats:p>","DOI":"10.1093\/hmg\/ddad042","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T13:53:16Z","timestamp":1678801996000},"page":"2068-2083","source":"Crossref","is-referenced-by-count":18,"title":["Human calmodulin mutations cause arrhythmia and affect neuronal function in\n                    <i>C. elegans<\/i>"],"prefix":"10.1093","volume":"32","author":[{"given":"Helene H","family":"Jensen","sequence":"first","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus T","family":"Frantzen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas L","family":"Wesseltoft","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Octavia","family":"Busuioc","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrine V","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malene","family":"Brohus","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palle R","family":"Duun","sequence":"additional","affiliation":[{"name":"Department of Health Science and Technology, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Nyegaard","sequence":"additional","affiliation":[{"name":"Department of Health Science and Technology, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T","family":"Overgaard","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Olsen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Bioscience, Aalborg University , Aalborg \u00d8 9220 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"2023062014135673200_ref1","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.cell.2007.11.028","article-title":"Calcium signaling","volume":"131","author":"Clapham","year":"2007","journal-title":"Cell"},{"key":"2023062014135673200_ref2","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm1155","article-title":"Calcium signalling: dynamics, homeostasis and remodelling","volume":"4","author":"Berridge","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023062014135673200_ref3","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2018.00396","article-title":"Human Calmodulin mutations","volume":"11","author":"Jensen","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"2023062014135673200_ref4","doi-asserted-by":"crossref","first-page":"5511","DOI":"10.1111\/febs.12337","article-title":"Calmodulin in a heartbeat","volume":"280","author":"Sorensen","year":"2013","journal-title":"FEBS J."},{"key":"2023062014135673200_ref5","doi-asserted-by":"crossref","first-page":"E1216","DOI":"10.1073\/pnas.1600385113","article-title":"Conserved properties of individual Ca2+-binding sites in calmodulin","volume":"113","author":"Halling","year":"2016","journal-title":"Proc. Natl. Acad. Sci."},{"key":"2023062014135673200_ref6","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.ajhg.2012.08.015","article-title":"Mutations in Calmodulin cause ventricular tachycardia and sudden cardiac death","volume":"91","author":"Nyegaard","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"2023062014135673200_ref7","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1161\/CIRCULATIONAHA.112.001216","article-title":"Calmodulin mutations associated with recurrent cardiac arrest in infants","volume":"127","author":"Crotti","year":"2013","journal-title":"Circulation"},{"key":"2023062014135673200_ref8","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1093\/eurheartj\/ehz311","article-title":"Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the international Calmodulinopathy registry","volume":"40","author":"Crotti","year":"2019","journal-title":"Eur. Heart J."},{"key":"2023062014135673200_ref9","first-page":"1","article-title":"Infanticide vs. inherited cardiac arrhythmias","volume":"23","author":"Brohus","year":"2020","journal-title":"EP Eur."},{"key":"2023062014135673200_ref10","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1093\/eurheartj\/ehz463","article-title":"The international Calmodulinopathy registry: recording the diverse phenotypic spectrum of un-CALM hearts","volume":"40","author":"Nyegaard","year":"2019","journal-title":"Eur. Heart J."},{"key":"2023062014135673200_ref11","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1093\/hmg\/ddx073","article-title":"Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation","volume":"26","author":"Yamamoto","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"2023062014135673200_ref12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1161\/CIRCRESAHA.116.309283","article-title":"A precision medicine approach to the rescue of function on malignant Calmodulinopathic long-QT syndrome","volume":"120","author":"Limpitikul","year":"2017","journal-title":"Circ. Res."},{"key":"2023062014135673200_ref13","doi-asserted-by":"crossref","first-page":"4554","DOI":"10.1111\/febs.14969","article-title":"Diminished inhibition and facilitated activation of RyR2-mediated Ca2+ release is a common defect of arrhythmogenic calmodulin mutations","volume":"286","author":"S\u00f8ndergaard","year":"2019","journal-title":"FEBS J."},{"key":"2023062014135673200_ref14","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.yjmcc.2014.04.022","article-title":"Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca2+ currents and promote proarrhythmic behavior in ventricular myocytes","volume":"74","author":"Limpitikul","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2023062014135673200_ref15","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1111\/febs.13184","article-title":"Calmodulin mutations causing catecholaminergic polymorphic ventricular tachycardia confer opposing functional and biophysical molecular changes","volume":"282","author":"S\u00f8ndergaard","year":"2015","journal-title":"FEBS J."},{"key":"2023062014135673200_ref16","doi-asserted-by":"crossref","first-page":"26636","DOI":"10.1074\/jbc.M116.758680","article-title":"The arrhythmogenic calmodulin mutation D129G dysregulates cell growth, calmodulin-dependent kinase II activity, and cardiac function in zebrafish","volume":"291","author":"Berchtold","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2023062014135673200_ref17","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1161\/CIRCULATIONAHA.120.046450","article-title":"Complex arrhythmia syndrome in a knock-in mouse model carrier of the N98S Calm1 mutation","volume":"142","author":"Tsai","year":"2020","journal-title":"Circulation"},{"key":"2023062014135673200_ref18","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1534\/genetics.115.176099","article-title":"A transparent window into biology: a primer on Caenorhabditis elegans","volume":"200","author":"Corsi","year":"2015","journal-title":"Genetics"},{"key":"2023062014135673200_ref19","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2022.691829","article-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","volume":"13","author":"Engel","year":"2022","journal-title":"Front. 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