BIOLOGICAL ANTIARRHYTHMICS-SODIUM CHANNEL INTERACTING PROTEINS.

Voltage gated Na channels (Na) are essential for excitation of tissues. Mutations in Nas cause a spectrum of human disease from autism and epilepsy to cardiac arrhythmias to skeletal myotonias. The carboxyl termini (CT) of Na channels are hotspots for disease-causing mutations and are richly invested with protein interaction sites. We have focused on the regulation of Na by two proteins that bind in this region: calmodulin (CaM) and non-secreted fibroblast growth factors (iFGF or FHF). CaM regulates Na gating, mediating Ca-dependent inactivation (CDI) in a channel isoform-specific manner, while Ca-free CaM (apo-CaM) binding broadly regulates Na opening and suppresses the arrhythmogenic late Na current (). FHFs inhibit CDI, in Na isoforms that exhibit this property, and potently suppress I, the latter requiring the amino terminus of the FHF. A peptide comprised of the first 39 amino acids of FHF1 is sufficient to inhibit I, constituting a credible specific antiarrhythmic.