Calmodulinopathy variants impair Ca_V1.3 and Ca_V2.1 regulation

Calmodulinopathies are caused by mutations in calmodulin (CaM) and result in debilitating cardiac arrythmias such as long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). In addition, many patients exhibit neurological comorbidities, including developmental delay and autism spectrum disorder. Prior studies have identified the impairment of Ca²⁺/CaM-dependent inactivation (CDI) of Ca_V1.2 channels as a major pathogenic mechanism leading to the LQTS phenotype in these patients. However, the impact of these mutations on other voltage-gated calcium channels (VGCCs) has yet to be fully explored. Here, we examine the potential for pathological CaM variants to impair the Ca²⁺/CaM-dependent regulation of Ca_V1.3 and Ca_V2.1, both essential for neuronal function. We find that pathogenic mutations in CaM can impair the CDI of Ca_V1.3, with overlapping yet distinct disruption of the Ca²⁺-dependent facilitation (CDF) of Ca_V2.1 channels. Moreover, while the majority of CaM variants demonstrated the ability to bind the IQ region of each channel, differences were noted between Ca_V1.3 and Ca_V2.1, demonstrating unique CaM interactions across the two channel subtypes. Further, C-lobe CaM variants display a reduced ability to sense Ca²⁺ when in complex with the Ca_V IQ domains, explaining the Ca²⁺/CaM regulation deficits. Overall, these results support the possibility that disrupted Ca²⁺/CaM regulation of multiple VGCCs may contribute to the pathogenesis of calmodulinopathies.