Disease-associated calmodulin variants impair regulation of neuronal voltage-gated calcium channels.

Abstract

Calmodulin (CaM) is a regulatory protein that associates with numerous binding partners, and it participates in key mechanisms by which multiple types of excitable cells sense and respond to changing levels of calcium. In neurons and cardiomyocytes, calcium ions flux into the cytosol through voltage-gated calcium channels (VGCCs) and bind to CaM. These binding events trigger an array of important feedback processes, including calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF) of multiple VGCC subtypes. In this way, CaM modulates VGCC activity and participates in calcium signaling cascades. Calmodulinopathies are a group of related disorders that arise from pathogenic mutations in CaM. These mutations alter cardiac calcium dynamics in a way that leads to debilitating disorders, including long-QT syndrome (LQTS). LQTS in calmodulinopathy patients has been shown to arise from the mutant forms of CaM preventing the protein from mediating proper CDI of cardiac CaV1.2 L-type channels. However, CaM regulation of VGCCs is not exclusive to the heart, and disruption of these processes in neuronal VGCCs may contribute to the comorbid neurological symptoms frequently observed in calmodulinopathy patients, including autism spectrum disorder, developmental delay, and seizures. We investigated the impacts of calmodulinopathic mutations on VGCCs known to be important for neuronal function. We found that CaM mutants caused diminished CDI in CaV1.3 channels similar to the deficit of CDI seen in CaV1.2 channels, as well as disruption of CDF in CaV2.1 channels. Interestingly, the pattern of CaV2.1 CDF disruptions by certain mutations does not entirely match the pattern seen in CaV1.2 and CaV1.3, indicating a differential effect of select mutations in this neuronal channel. Overall, our results suggest that calmodulinopathic mutations may have consequences to calcium dynamics that extend into neural tissues, in addition to their well-described impacts on cardiac health.