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Regulation of the Human Ether‐a‐go‐go Related Gene (hERG) Potassium Channel by Nedd4 Family Interacting Proteins (Ndfips)
Author(s) -
KANG YUDI,
Guo Jun,
Yang Tonghua,
Li Wentao,
Zhang Shetuan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.714.4
Subject(s) - herg , nedd4 , microbiology and biotechnology , potassium channel , ubiquitin ligase , ion channel , ubiquitin , chemistry , cardiac action potential , hek 293 cells , biology , biochemistry , gene , neuroscience , electrophysiology , repolarization , biophysics , receptor
The cardiac electrical disorder long QT syndrome (LQTS) predisposes affected individuals to high risks of ventricular arrhythmias and sudden death. Dysfunction of the human ether‐a‐go‐go related gene (hERG)‐encoded rapidly activating delayed rectifier K + channel (I Kr ) is a major cause of LQTS. The expression of hERG channels is controlled by the anterograde trafficking of newly synthesized channels to and the retrograde degradation of existing channels from the plasma membrane. We have previously shown that the E3 ubiquitin ligase Nedd4‐2 (neuronal precursor cell expressed, developmentally down‐regulated protein 4 type 2) targets the PY motif of hERG channels to initiate channel degradation. Although both premature and mature hERG channels contain the PY motif, Nedd4‐2 selectively mediates the degradation of mature hERG channels. Here, using whole‐cell patch clamp, Western blot and immunocytochemical analyses, we demonstrate that Nedd4‐2 is directed to specific cellular compartments by the Nedd4 family interacting proteins, Ndfip1 and Ndfip2. Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4‐2 to target mature hERG proteins for degradation during channel trafficking to the plasma membrane. Although Ndfip2 also recruits Nedd4‐2 to the Golgi apparatus to some extent, it mainly recruits Nedd4‐2 to the multivesicular bodies (MVBs), which impedes the degradation of internalized hERG proteins. These findings extend our understanding of hERG channel regulation and provide information which may be useful for the rescue of impaired hERG function in LQTS. (Supported by the Natural Sciences and Engineering Research Council of Canada and the Heart and Stroke Foundation of Ontario)