期刊
FASEB JOURNAL
卷 27, 期 2, 页码 622-631出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.12-214387
关键词
cardiac; voltage-gated potassium channel; arrhythmias; N-glycosylation; ion channel; sialylation
资金
- American Heart Association
- James and Esther King Florida Biomedical Research Program
- U.S. National Science Foundation
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [1146882] Funding Source: National Science Foundation
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 similar to 9 and similar to 18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing similar to 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
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