Human calmodulin mutations cause arrhythmia and affect neuronal function in C. elegans

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.

Automated summary

Mutations in calmodulin in humans can cause cardiac arrhythmia by disrupting calcium sensing and regulation of calcium channels, leading to abnormal heart rhythm. However, the effects of these mutations on other tissues and neuronal function have been largely unexplored. In this study, the nematode C. elegans was used as a model organism to study the effects of three calmodulin mutations on calcium binding. The results showed that these mutations not only affect rhythmic behaviors but also have different effects on neuronal function, suggesting that calmodulin mutations may also contribute to neurological diseases.