Modulation of cardiac sodium channel gating by protein kinase A can be altered by disease-linked mutation.
Mutations associated with sodium channel-linked inherited Long-QT syndrome often result in a gain of channel function by disrupting channel inactivation. A small fraction of channels fail to inactivate (burst) at depolarized potentials where normal (wild type) channels fully inactivate. These noninactivating channels give rise to a sustained macroscopic current. We studied the effects of protein kinase A stimulation on sustained current in wild type and three disease-linked C-terminal mutant channels (D1790G, Y1795C, and Y1795H). We show that protein kinase A stimulation differentially affects gating in the mutant channels. Wild type, Y1795C, and Y1795H channels are insensitive to protein kinase A stimulation, whereas "bursting" in the D1790G mutant is markedly enhanced by protein kinase A-dependent phosphorylation. Our results suggest that the charge at position 1790 of the C terminus of the channel modulates the response of the cardiac sodium channel to protein kinase A stimulation and that phosphorylation of residue 36 in the N terminus and residue 525 in the cytoplasmic linker joining domains I and II of the channel alpha subunit facilitate destabilization of inactivation and thereby increase sustained current.
D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics*; D008564:Membrane Potentials; D020125:Mutation, Missense / Q000502:physiology*; D009206:Myocardium / Q000737:chemistry*; D010766:Phosphorylation; D015222:Sodium Channels; D014162:Transfection
D015222:Sodium Channels; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases