Dual Role of CACNA1C/CaV1.2 in Cardiac and Neuropsychiatric Disease

The CACNA1C gene encodes the α1C subunit of voltage-gated CaV1.2 calcium channels, serving many pivotal functions throughout the body, including in the heart and brain. Clinical and genetic evidence implicates altered expression and/or function of CACNA1C/CaV1.2 in both cardiac and neuropsychiatric disease, including hypertension, cardiac arrhythmias, coronary artery disease, schizophrenia, bipolar disorder, depression, and autism. Gain-of-function mutations in CACNA1C cause Timothy syndrome, a potentially lethal multi-organ disorder with severe cardiac and neuropsychiatric defects. Conversely, the complete loss of Cacna1c is lethal in mice. The development of viable mouse and rat models with Cacna1c haploinsufficiency has allowed us to study the consequences of reduced expression and function of Cacna1c/CaV1.2 for heart and brain function from the molecular and cellular to the behavioral level. We review recent findings from these rodent models, revealing (i) alterations in behavior and (ii) in neuronal and non-neuronal function, as well as (iii) an impaired ability of the heart and its cardiomyocytes to adapt to (sympathetic) stress. Results lend further support to the notion that CACNA1C/CaV1.2 dysfunction represents a common link between cardiac and neuropsychiatric disorders and that appropriately targeting CACNA1C/CaV1.2 in selected patients may hold the promise of treating both conditions effectively with a single drug.