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Activation of muscarinic receptor increases cardiac potassium hERG channel through phosphorylation of E3 ubiquitin ligase Nedd4–2
Author(s) -
Wang Tingzhong,
Zhang Shetuan
Publication year - 2013
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.27.1_supplement.553.14
Subject(s) - herg , chemistry , muscarinic acetylcholine receptor , oxotremorine , pharmacology , carbachol , potassium channel , muscarinic agonist , ubiquitin ligase , ryanodine receptor , endocrinology , receptor , biology , biochemistry , ubiquitin , gene
The human ether‐a‐go‐go‐related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel ( I Kr ) which is critical for repolarization of cardiac action potential. Loss of function of hERG channels due to gene mutations or drug blockade causes long QT syndrome. Presently, little is known about the restoration or enhancement of hERG channel function. In the present study, we found that muscarinic receptor agonist, carbachol, specifically increased hERG expression and I hERG , but had no effect on I Ks , I EAG and I Kv1.5 channels in HEK expression systems. Carbachol treatment decreased hERG‐ubiquitin interaction and hERG degradation. It is known that hERG channels are degraded by the Nedd4–2, we found that disrupting the binding sites of Nedd4–2 by the Y1078A point mutation or C‐terminal truncation Δ1073 mutation in hERG completely eliminated the effects of carbachol on hERG channels. Our data further indicate that carbachol treatment inhibited Nedd4–2 activity by enhancing its phosphorylation level. Another muscarinic receptor agonist, oxotremorine, increased hERG function, and the muscarinic receptor antagonist 4‐DAMP abolished the effects of both carbachol and oxotremorine on hERG channels. Enhancement of hERG function by muscarinic receptor activation represents a novel pathway in hERG regulation, and this finding may have potential for the management of long QT syndrome patients. Supported by: Canadian Institutes of Health Research (CIHR).