Ca²⁺ channelopathies have been described for Ca_v1.1, Ca_v1.2 and Ca_v1.4 L-type channels (LTCCs) and recently also for Ca_v1.3. The latter translate sound-induced depolarization into neurotransmitter release in auditory hair cells, and control diastolic depolarization in mouse sinoatrial. In humans a glycine insertion mutation was identified in two consanguineous deafness families. All patients exhibited pronounced SAN dysfunction at rest. The insertion of a glycine residue in a highly conserved alternatively spliced region near the pore resulted in non-conducting calcium channels and altered voltage-dependent gating. In some patients with Timothy syndrome, the corresponding glycine is mutated to serine in Ca_v1.2 LTCCs. The resulting functional changes were evident as pronounced slowing of voltage-dependent inactivation. Replacement of the corresponding glycine residue by aspartate in human Ca_v1.4 LTCCs similarly resulted in significant gain-of-function with a shift of channel activation to more negative voltages and slowed channel inactivation. Patients carrying this mutation suffer from X-linked recessive congenital stationary night blindness (CSNB2). Moreover, other CSNB2-causing Ca_v1.4 mutations led to the discovery of a novel intramolecular protein interaction by which LTCCs modulate their gating behavior. This opened a new field of research also on Ca_v1.3 channels which use this mechanism to adjust their activity by intracellular Ca²⁺ activity and alternative splicing. Given their delicate role in the pathophysiology of Parkinson's disease this mechanism may also become a target for the development of novel therapies.