Mutations within the genes encoding pore forming a1-subunits of voltage-gated L-type Ca²⁺ channels (Cav1 channels) give rise to different human diseases thereby providing exciting new insight into functionally relevant structural features of these channels. For example, voltage-sensor mutations in skeletal muscle Cav1.1 channels (CACNA1S) cause Hypokalemic Periodic Paralysis by creating an aberrant ion pore resulting in depolarizing leak currents. Sporadic Cav1.2 (CACNA1C) mutations in IS6 helices cause Timothy Syndrome (a multisystem disorder including long-QT interval and sudden cardiac death) by slowing voltage-and Ca²⁺-dependent inactivation. Congenital stationary night blindness type 2 results from loss-of function mutations in Cav1.4 (CACNA1F) channels which trigger glutamate release from retinal photoreceptor terminals. A mutation partially truncating the long C-terminal tail revealed an intramolecular protein-protein interaction within the C-terminus that turns off calmodulin-mediated Ca²⁺-dependent inactivation of Cav1.4 channels to permit the prolonged Ca²⁺ influx required for photoreceptor signaling. This observation led to the discovery of a similar regulatory mechanism in Cav1.3 channels in which a distal helical domain interacts with a more proximal one within the C-terminal tail. This moderates Ca²⁺-dependent inactivation of Cav1.3 and shifts the activation voltage-dependence to more positive voltages. The distal domain is absent in short Cav1.3 splice variants, explaining their more negative activation range and faster inactivation. Therefore alternative splicing enables Cav1.3 channels to adjust their biophysical properties to different cellular needs, such as for their known pacemaker function in heart and neurons, including dopaminergic substantia nigra neurons. We have recently discovered a novel human disease (SANDD) resulting from a loss-of-function mutation in the Ca_v1.3 a1-subunit gene (CACNA1D). Affected individuals suffer from congenital deafness and sinoatrial node dysfunction, emphasizing the important role of these channels for cardiac pacemaking and neurotransmitter release in sensory cells. (Support: FWF P20670, University of Innsbruck; Geers-Stiftung, Bonn; Imhoff-Stiftung, Köln; Köln Fortune, University Hospital of Cologne)