Calmodulin (CaM) is a ubiquitous calcium sensor, vital to immune system, heart and brain function. Mutations within CaM result in a set of disorders known as calmodulinopathies. Patients harboring these CaM mutations suffer from life-threatening cardiac arrhythmias, which are often accompanied by neurodevelopmental delay or other neurological dysfunction. While CaM has numerous potential targets which may be altered in calmodulinopathies, voltage gated calcium channels (VGCCs) stand out as likely pathogenic elements. For CaV1-2 channels, CaM is known to preassociate with the carboxy-tail of the channel. Upon binding Ca2+, this resident CaM initiates either of two important forms of feedback regulation; Ca2+/CaM dependent inactivation (CDI) or Ca2+/CaM dependent facilitation (CDF). Each of these forms of channel regulation can be independently driven by a single lobe of CaM, with CaV1.2, CaV1.3 and CaV2.1 each strongly modulated by Ca2+ binding to the C-lobe of CaM. As the majority of calmodulinopathy mutations have thus-far impacted the CaM C-lobe, this lobe-specific regulation implies a large impact of calmodulinopathy mutations on the regulation of these three channels. In fact, we have previously demonstrated that calmodulinopathy mutations are capable of disrupting the CDI of CaV1.2 channels, resulting in the long-QT phenotype seen in patients6,7. However, the effect of CaM mutations on VGCCs other than CaV1.2 has yet to be elucidated, nor have the mechanisms underlying the neurological phenotypes of calmodulinopathy patients been explored. As CaV1-2 channels play critical roles in neuronal excitability, excitation-transcription coupling, and neurotransmission, we propose that they are likely contributors to the neuropathogenesis of calmodulinopathies. We will therefore undertake a biophysical study of the impact of calmodulinopathy mutations across the CaV1-2 channel family and evaluate the impact of these mutations on neuronal function. In particular, we hypothesize that CaM mutations which alter the Ca2+ binding to the C-lobe of the protein will decrease CDI in CaV1.2 and CaV1.3, and disrupt CDF in CaV2.1. To evaluate the functional impact of these mutations, we will generate induced pluripotent stem cell derived neurons (iPSC-neurons) from calmodulinopathy patients, and elucidate a cellular phenotype correlating with the neurological deficits of calmodulinopathy patients. Thus, we will undertake one of the first studies aimed at understanding the impact of calmodulinopathy mutations outside the heart, expanding our understanding of the pathogenic mechanisms underlying this disorder.