Biological antiarrhythmics-sodium channel interacting proteins

Trans Am Clin Climatol Assoc. 2023;133:136-148.ABSTRACTVoltage gated Na channels (NaV) are essential for excitation of tissues. Mutations in NaVs cause a spectrum of human disease from autism and epilepsy to cardiac arrhythmias to skeletal myotonias. The carboxyl termini (CT) of NaV channels are hotspots for disease-causing mutations and are richly invested with protein interaction sites. We have focused on the regulation of NaV by two proteins that bind in this region: calmodulin (CaM) and non-secreted fibroblast growth factors (iFGF or FHF). CaM regulates NaV gating, mediating Ca2+-dependent inactivation (CDI) in a channel isoform-specific manner, while Ca2+-free CaM (apo-CaM) binding broadly regulates NaV opening and suppresses the arrhythmogenic late Na current (INa-L). FHFs inhibit CDI, in NaV isoforms that exhibit this property, and potently suppress INa-L, the latter requiring the amino terminus of the FHF. A peptide comprised of the first 39 amino acids of FHF1A is sufficient to inhibit INa-L, constituting a credible specific antiarrhythmic.PMID:37701589
Source: Transactions of the American Clinical and Climatological Association - Category: General Medicine Authors: Source Type: research