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

Abstract

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.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry

“…There are patients who present with both abnormalities, and we observed one CALM -related neurological/neurodevelopmental phenotype in the absence of any cardiac features. Indeed, human arrhythmic CALM variants have now been demonstrated to both cause arrhythmic behaviour and affect neuronal function in Caenorhabditis elegans , 20 supporting a fundamental evolutionary critical link between CALM integrity and optimal neurodevelopment.…”

Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects

“…Studies from cell culture and mouse models show that depletion of specific CALM transcript variants prevents neuronal migration and brain development (46, 47), and competitive removal of calmodulin protein in developing neurons in Drosophila melanogaster disrupted axonal development in the neural growth cone (48). Furthermore, in a Caenorhabditis elegans model, we have demonstrated that human calmodulin variants from cardiac patients have neurological consequences (49, 50). As such, the impact of calmodulin variants in the brain may be multifaceted and highly complex and we have likely only seen the tip of the iceberg.…”

Identifying Key Binding Interactions Between the Cardiac L-Type Calcium Channel and Calmodulin Using Molecular Dynamics Simulations

“…At the whole cell, tissue, and organism levels, the downstream spatial and temporal effects of CaM mutations have been shown to be factors in disease phenotype. For instance, Jensen et al 52 studied the effect of the CPVT specific N54I mutation and LQTS specific D96V mutation on Caenorhabditis Elegans . The authors observed alterations in two different rhythmic processes: pharynx pumping and the defecation motor program.…”