BIOLOGICAL ANTIARRHYTHMICS-SODIUM CHANNEL INTERACTING PROTEINS.

Abstract

Voltage gated Na channels (Na_V) are essential for excitation of tissues. Mutations in Na_Vs cause a spectrum of human disease from autism and epilepsy to cardiac arrhythmias to skeletal myotonias. The carboxyl termini (CT) of Na_V channels are hotspots for disease-causing mutations and are richly invested with protein interaction sites. We have focused on the regulation of Na_V by two proteins that bind in this region: calmodulin (CaM) and non-secreted fibroblast growth factors (iFGF or FHF). CaM regulates Na_V gating, mediating Ca²⁺-dependent inactivation (CDI) in a channel isoform-specific manner, while Ca²⁺-free CaM (apo-CaM) binding broadly regulates Na_V opening and suppresses the arrhythmogenic late Na current (I_Na-L). FHFs inhibit CDI, in Na_V isoforms that exhibit this property, and potently suppress I_Na-L, the latter requiring the amino terminus of the FHF. A peptide comprised of the first 39 amino acids of FHF1_A is sufficient to inhibit I_Na-L, constituting a credible specific antiarrhythmic.