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Channel sialic acids limit hERG channel activity during the ventricular action potential
Author(s) -
Norring Sarah A.,
Ednie Andrew R.,
Schwetz Tara A.,
Du Dongping,
Yang Hui,
Bennett Eric S.
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/fj.12-214387
Subject(s) - herg , chemistry , repolarization , chinese hamster ovary cell , cardiac action potential , gating , ventricular action potential , depolarization , biophysics , membrane potential , voltage clamp , patch clamp , pharmacology , electrophysiology , mechanism of action , potassium channel , biochemistry , medicine , biology , receptor , in vitro
Activity of human ether‐a‐go‐go‐ related gene (hERG) 1 voltage‐gated K + channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N ‐glycosylation modified hERG channel function. Voltage‐dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N ‐glycans, and following enzymatic deglycosylation of surface N ‐glycans. For each condition of reduced glycosylation, hERG channel steady‐state activation and inactivation relationships were shifted linearly by significant depolarizing ~9 and ~18 mV, respectively. The hERG window current increased significantly by 50‐150%, and the peak shifted by a depolarizing ~10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20–80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50‐70‐ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N ‐glycosylation; reduced channel sialylation increases hERG channel activity during the action potential, thereby increasing the rate of action potential repolarization.—Norring, S. A., Ednie, A. R., Schwetz, T. A., Du, D., Yang, H., Bennett, E. S. Channel sialic acids limit hERG channel activity during the ventricular action potential. FASEB J. 27, 622–631 (2013). www.fasebj.org