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.

Tateyama, M., Rivolta, I., Clancy, C., & Kass, R. (2003). Modulation of cardiac sodium channel gating by protein kinase A can be altered by disease-linked mutation. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 278(47), 46718-46726 [10.1074/jbc.M308977200].

Modulation of cardiac sodium channel gating by protein kinase A can be altered by disease-linked mutation

Rivolta, I;
2003

Abstract

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.
Articolo in rivista - Articolo scientifico
Scientifica
Ion Channel Gating; Humans; Cyclic AMP; Electrophysiology; Mutation, Missense; Sodium Channels; Phosphorylation; Transfection; Membrane Potentials; Long QT Syndrome; Cyclic AMP-Dependent Protein Kinases; Cell Line; Myocardium
English
Tateyama, M., Rivolta, I., Clancy, C., & Kass, R. (2003). Modulation of cardiac sodium channel gating by protein kinase A can be altered by disease-linked mutation. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 278(47), 46718-46726 [10.1074/jbc.M308977200].
Tateyama, M; Rivolta, I; Clancy, C; Kass, R
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/274361
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