Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG/KCNH2 proteins in the heart
Reduced levels of hERG protein and the corresponding repolarizing current IKr can cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood. We identified TRIOBP-1, an F-actin binding protein previously associated wi...
Elmentve itt :
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| Dokumentumtípus: | Cikk |
| Megjelent: |
2018
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| Sorozat: | JOURNAL OF CELL SCIENCE
131 No. 6 |
| doi: | 10.1242/jcs.206730 |
| mtmt: | 3346396 |
| Online Access: | http://publicatio.bibl.u-szeged.hu/16235 |
| Tartalmi kivonat: | Reduced levels of hERG protein and the corresponding repolarizing current IKr can cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood. We identified TRIOBP-1, an F-actin binding protein previously associated with actin polymerization, as a putative hERG-interacting protein in a yeast-two hybrid screen of a cardiac library. We corroborated this interaction using Forster resonance energy transfer (FRET) in HEK293 cells and co-immunoprecipitation in HEK293 cells and native cardiac tissue. TRIOBP-1 overexpression reduced hERG surface expression and current density, whereas reducing TRIOBP-1 expression via shRNA knockdown resulted in increased hERG protein levels. Immunolabeling in rat cardiomyocytes showed that native TRIOBP-1 overlapped predominantly with myosin binding protein C and secondarily with rat ERG. In human stem cell-derived cardiomyocytes, TRIOBP-1 overexpression caused intracellular co-sequestration of hERG signal, reduced native IKr, and disrupted action potential repolarization. Calcium currents were also reduced to a lesser degree and cell capacitance was increased. These findings establish that TRIOBP-1 interacts directly with hERG and can affect protein levels, IKr magnitude, and cardiac membrane excitability. |
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| Terjedelem/Fizikai jellemzők: | Paper jcs206730-12 p |
| ISSN: | 0021-9533 |