Abstract 14053: Sumoylation of the Cardiac Sodium Channel Na V 1.5 Does Not Increase Late Sodium Current
Abstract only Introduction: The sodium current (I Na ) controlling cardiac cell excitability is conducted via the Na + channel Na V 1.5 (encoded by SCN5A ). Dysregulation of Na V 1.5 has been implicated in arrhythmia, with increased late Na V 1.5 current (I Na,L ) causing long QT type 3. Many Na V 1...
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Published in | Circulation (New York, N.Y.) Vol. 144; no. Suppl_1 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
16.11.2021
|
Online Access | Get full text |
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Summary: | Abstract only
Introduction:
The sodium current (I
Na
) controlling cardiac cell excitability is conducted via the Na
+
channel Na
V
1.5 (encoded by
SCN5A
). Dysregulation of Na
V
1.5 has been implicated in arrhythmia, with increased late Na
V
1.5 current (I
Na,L
) causing long QT type 3. Many Na
V
1.5 post-translational modifications have been reported by us and others, including SUMOylation, the addition of a Small Ubiquitin-like MOdifier (SUMO) at K442-Na
V
1.5. Plant et al. (2020) recently reported that hypoxia increases I
Na,L
by increased Na
V
1.5 SUMOylation.
Hypothesis:
SUMOylation modifies peak but not late Na
V
1.5 currents through membrane localization.
Methods:
SUMOylation of Na
V
1.5 by SUMO1 was detected by immunoprecipitation and immunoblot. The effects of SUMOylation on peak I
Na
and I
Na,L
were measured using patch clamp in HEK293 cells transfected with wild type (WT) or mutant K442R-Na
V
1.5 with/without the β1 subunit and in neonatal rat cardiac myocytes (NRCMs). Tetrodotoxin (TTX) was used to quantitate I
Na,L
in NRCMs. Na
V
1.5 trafficking was detected by immunofluorescence.
Results:
Na
V
1.5 was SUMOylated by SUMO1 in HEK cells, NRCMs, and human heart samples. Overexpressing or directly applying SUMO1 induced hyperSUMOylation of Na
V
1.5 at K442 and increased the amplitude of peak I
Na
in NRCMs and in HEK cells overexpressing WT but not K442R-Na
v
1.5. SUMOylation did not affect I
Na,L
in HEK293 cells expressing Na
V
1.5 with/without the β1 subunit or in NRCMs (Fig. 1A, B). SUMO1 enhanced membrane localization of Na
V
1.5 in HEK293 cells (Fig. 1C) with minimal changes to steady state activation, inactivation or channel kinetics.
Conclusion:
SUMOylation of Na
v
1.5 at K442 increases peak I
Na
without changing I
Na,L
, at least in part by altering membrane abundance. Our findings do not support SUMOylation as a mechanism for changes in I
Na,L
. |
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ISSN: | 0009-7322 1524-4539 |
DOI: | 10.1161/circ.144.suppl_1.14053 |