Mutations in the genes of voltage-gated Ca²⁺ channel subunits (Ca²⁺ channelopathies) cause diseases in mice and humans. Although human mutations are rare, they provide a unique molecular approach to study the role of different channel isoforms for pathological processes underlying diseases such as migraine, epilepsy, ataxia, night blindness, cardiac arrhythmias and autism. CSNB2, an X-linked recessive congenital form of night blindness, is caused by mutations of retinal Ca_v1.4 a1 subunits. We investigated the functional consequences of CSNB2 mutations by electrophysiological analysis after heterologous expression in HEK-293T cells. We found that structural aberrations reduce channel function to various degrees and through different mechanisms. A C-terminal truncation mutant (K1591X) unmasked a novel regulatory mechanisms that controls the voltage- and Ca²⁺ -dependent gating of Ca_v1.4 as well as other L-type Ca²⁺ -channels. In Ca _v1.4 channels the last 55 amino acid residues participate in the formation of a C-terminal modulatory structure which completely prevents the Ca²⁺ -dependent inactivation of Ca_v1.4 and shifts channel activation to more positive voltages. FRET analysis revealed binding of this C-terminal peptide to proximal regions of the C-terminus known to serve as interaction sites for calmodulin. Our data represent an excellent example of how channelopathies can provide unique insight into Ca_v1.4 Ca²⁺ channel function. We will provide evidence that a similar C-terminal modulatory mechanism also controls the function of other L-type channels. A more detailed understanding of this intramolecular protein-protein interaction may lead to novel concepts for the selective modulation of Ca²⁺ -channel function by drugs.

Support: Austrian Sci. Fund FWF17159, P-17109, P-15387, P-16537), Univ. Innsbruck, Tiroler Wissenschaftsfond