Abstract
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. Until now, most work into these mutations has focused on cardiac effects, identifying impairment of Ca (2+) /CaM-dependent inactivation (CDI) of Ca (V) 1.2 channels as a major pathogenic mechanism. However, the impact of these mutations on neurological function has yet to be fully explored. CaM regulation of voltage-gated calcium channels (VGCCs) is a critical element of neuronal function, implicating multiple VGCC subtypes in the neurological pathogenesis of calmodulinopathies. Here, we explore the potential for pathological CaM variants to impair the Ca (2+) /CaM-dependent regulation of Ca (V) 1.3 and Ca (V) 2.1, both essential for neuronal function. We find that mutations in CaM can impair the CDI of Ca (V) 1.3 and reduce the Ca (2+) -dependent facilitation (CDF) of Ca (V) 2.1 channels. We find that mutations associated with significant neurological symptoms exhibit marked effects on Ca (V) 1.3 CDI, with overlapping but distinct impacts on Ca (V) 2.1 CDF. Moreover, while the majority of CaM variants demonstrated the ability to bind the IQ region of each channel, distinct differences were noted between Ca (V) 1.3 and Ca (V) 2.1, demonstrating distinct CaM interactions across the two channel subtypes. Further, C-domain CaM variants display a reduced ability to sense Ca (2+) when in complex with the Ca (V) IQ domains, explaining the Ca (2+) /CaM regulation deficits. Overall, these results support the possibility that disrupted Ca (2+) /CaM regulation of VGCCs may contribute to neurological pathogenesis of calmodulinopathies.