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 Citations (Scopus)

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

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Sialic Acids
Ether
Action Potentials
Genes
Glycosylation
Polysaccharides
Voltage-Gated Potassium Channels
Phase control
Clamping devices
Cricetulus
Human Activities
Ovary
Current density
Chemical activation
Cells
Cell Line

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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
Norring, Sarah A. ; Ednie, Andrew R. ; Schwetz, Tara A. ; Du, Dongping ; Yang, Hui ; Bennett, Eric S. / Channel sialic acids limit hERG channel activity during the ventricular action potential. In: FASEB Journal. 2013 ; Vol. 27, No. 2. pp. 622-631.
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Norring, SA, Ednie, AR, Schwetz, TA, Du, D, Yang, H & Bennett, ES 2013, 'Channel sialic acids limit hERG channel activity during the ventricular action potential', FASEB Journal, vol. 27, no. 2, pp. 622-631. https://doi.org/10.1096/fj.12-214387

Channel sialic acids limit hERG channel activity during the ventricular action potential. / Norring, Sarah A.; Ednie, Andrew R.; Schwetz, Tara A.; Du, Dongping; Yang, Hui; Bennett, Eric S.

In: FASEB Journal, Vol. 27, No. 2, 01.02.2013, p. 622-631.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Channel sialic acids limit hERG channel activity during the ventricular action potential

AU - Norring, Sarah A.

AU - Ednie, Andrew R.

AU - Schwetz, Tara A.

AU - Du, Dongping

AU - Yang, Hui

AU - Bennett, Eric S.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

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