L-type calcium channel disease

The discovery of the role of voltage-gated L-type calcium channels (LTCC) as a cause of cardiac channelopathies is one of the most relevant advancements in the field of arrhythmology. LTCC defects have been identified with delay as compared with mutation in other potassium or sodium channels. A possible explanation relies on the complex genetic architecture of LTCC, which made difficult to plan and perform detailed investigations. The contribution of different gene/proteins is required in order to recapitulate a fully functional calcium conducting multimerical complex and mutations have been identified in different channel subunits. Functionally, LTCC have a key role in cardiac excitability, therefore it is not surprising that they may cause multiple and often severe clinical phenotypes: Timothy syndrome, Brugada syndrome, short QT syndrome, early repolarization and J wave syndromes. In this chapter we present an overview of the structure, physiology and pathophysiology of the cardiac Cav1.2 encoded by the CACNA1c gene with a specific focus on Timothy syndrome.