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 α subunit facilitate destabilization of inactivation and thereby increase sustained current.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 46718-46726 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 278 |
| Issue number | 47 |
| DOIs | |
| State | Published - Nov 21 2003 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Modulation of Cardiac Sodium Channel Gating by Protein Kinase A Can Be Altered by Disease-linked Mutation. / Tateyama, Michihiro; Rivolta, Ilaria; Clancy, Colleen E; Kass, Robert S.
In: Journal of Biological Chemistry, Vol. 278, No. 47, 21.11.2003, p. 46718-46726.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Modulation of Cardiac Sodium Channel Gating by Protein Kinase A Can Be Altered by Disease-linked Mutation
AU - Tateyama, Michihiro
AU - Rivolta, Ilaria
AU - Clancy, Colleen E
AU - Kass, Robert S.
PY - 2003/11/21
Y1 - 2003/11/21
N2 - 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 α subunit facilitate destabilization of inactivation and thereby increase sustained current.
AB - 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 α subunit facilitate destabilization of inactivation and thereby increase sustained current.
UR - http://www.scopus.com/inward/record.url?scp=0344012531&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0344012531&partnerID=8YFLogxK
U2 - 10.1074/jbc.M308977200
DO - 10.1074/jbc.M308977200
M3 - Article
C2 - 14500710
AN - SCOPUS:0344012531
VL - 278
SP - 46718
EP - 46726
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 47
ER -