Channel sialic acids limit hERG channel activity during the ventricular action potential

Sarah A. Norring, Andrew R. Ednie, Tara A. Schwetz, Dongping Du, Hui Yang, Eric S. Bennett

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)622-631
Number of pages10
JournalFASEB Journal
Volume27
Issue number2
DOIs
StatePublished - Feb 1 2013

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Norring, S. A., Ednie, A. R., Schwetz, T. A., Du, D., Yang, H., & Bennett, E. S. (2013). Channel sialic acids limit hERG channel activity during the ventricular action potential. FASEB Journal, 27(2), 622-631. https://doi.org/10.1096/fj.12-214387