CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency

Mutations of human Ca(V)1.2 channel gene were identified only recently. The gain-of-function mutations were found at two mutually exclusive exons in patients with Timothy syndrome (TS). These patients exhibit prolonged QT interval and lethal cardiac arrhythmias. In contrast, the loss-of-function mutations of Ca(V)1.2 channel in patients with Brugada syndrome produce short QT interval that could result in sudden cardiac death. TS patients also suffer from multi-organ dysfunction that includes neurological disorder such as autism and mental retardation reflecting the wide tissue distribution of Ca(V)1.2 channel. Mutations found on different mutually exclusive exons determine the severity of the disease. Unexpectedly, TS patients may develop recurrent infections and bronchitis that suggests a role of Ca(V)1.2 channel in the immune system. Furthermore, recent reports revealed a linkage of Ca(V)1.2 channel polymorphism with multiple central nervous system disorders including bipolar disorder, depression, and schizophrenia. Here, we will discuss how alternative splicing modulates Ca(V)1.2 channelopathy and the role of Ca(V)1.2 channel in both excitable and non-excitable tissues.