Voltage Gated Calcium Channel Dysregulation May Contribute to Neurological Symptoms in Calmodulinopathies

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 Ca2+/CaM-dependent inactivation (CDI) of CaV1.2 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 Ca2+/CaM-dependent regulation of CaV1.3 and CaV2.1, both essential for neuronal function. We find that mutations in CaM can impair the CDI of CaV1.3 and reduce the Ca2+-dependent facilitation (CDF) of CaV2.1 channels. We find that mutations associated with significant neurological symptoms exhibit marked effects on CaV1.3 CDI, with overlapping but distinct impacts on CaV2.1 CDF. Moreover, while the majority of CaM variants demonstrated the ability to bind the IQ region of each channel, distinct differences were noted between CaV1.3 and CaV2.1, demonstrating distinct CaM interactions across the two channel subtypes. Further, C-domain CaM variants display a reduced ability to sense Ca2+ when in complex with the CaV IQ domains, explaining the Ca2+/CaM regulation deficits. Overall, these results support the possibility that disrupted Ca2+/CaM regulation of VGCCs may contribute to neurological pathogenesis of calmodulinopathies.