Sialic Acids Attached to O-Glycans Modulate Voltage-gated Potassium Channel Gating

Schwetz, Tara A.; Norring, Sarah A.; Ednie, Andrew R.; Bennett, Eric S.

doi:10.1074/jbc.m110.171322

Cited by 52 publications

(51 citation statements)

References 65 publications

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“…There is some evidence of a role for K v 4.3; however, genetic ablation of the corresponding gene had no impact on mouse ventricular I K or repolarization, suggesting a minimal contribution from this isoform (24). K v 4.2 and K v 2.1 were shown to possess O-linked glycans with no N-linked sites, whereas the K v 1.5 isoform contains one putatively occupied N-linked site, and it is unknown whether there are occupied O-linked sites (12,14,26). Molecularly, I SS is likely conducted predominately through non-voltage-dependent channels of the "two-pore" type (K 2P ) (27).…”

mentioning

confidence: 99%

Reduced Sialylation Impacts Ventricular Repolarization by Modulating Specific K+ Channel Isoforms Distinctly

Ednie

Bennett

2015

Journal of Biological Chemistry

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confidence: 99%

Reduced Sialylation Impacts Ventricular Repolarization by Modulating Specific K+ Channel Isoforms Distinctly

Ednie

Bennett

2015

Journal of Biological Chemistry

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“…Tunicamycin and glycosidase treatments indicated that K v 2.1 is not N-glycosylated [41]. Although, K v 2.1, K v 4.3, and K v 4.2 are not N-glycosylated, they have shown depolarization shifts in the absence of sialylation [37,42]. This change suggests that O-linked sialylation is present and affects G-V shifts.…”

Section: Potassium Channelsmentioning

confidence: 99%

“…Recently, it is shown that O-linked sialylation can have an impact on channel depolarization. However, it does not affect the steady-state inactivation and/or rate of recovery from fast inactivation [42]. …”

Section: Potassium Channelsmentioning

confidence: 99%

Physiologic and pathophysiologic consequences of altered sialylation and glycosylation on ion channel function

Baycin-Hizal

Gottschalk

Jacobson

et al. 2014

Biochemical and Biophysical Research Communications

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Voltage-gated ion channels are transmembrane proteins that regulate electrical excitability in cells and are essential components of the electrically active tissues of nerves, muscle and the heart. Potassium channels are one of the largest subfamilies of voltage sensitive channels and are among the most-studied of the voltage-gated ion channels. Voltage-gated channels can be glycosylated and changes in the glycosylation pattern can affect ion channel function, leading to neurological and neuromuscular disorders and congenital disorders of glycosylation (CDG). Alterations in glycosylation can also be acquired and appear to play a role in development and aging. Recent studies have focused on the impact of glycosylation and sialylation on ion channels, particularly for voltage-gated potassium and sodium channels. The terminal step of sialylation often affects channel activation and inactivation kinetics. The presence of sialic acids on O or N-glycans can alter the gating mechanism and cause conformational changes in the voltage-sensing domains due to sialic acid's negative charges. This manuscript will provide an overview of sialic acids, potassium and sodium channel function, and the impact of sialylation on channel activation and deactivation.

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“…O-glycans can also contribute to voltage-gated ion channel activity, at least to K v channel activity [13, 38]. Here we question whether sialic acids attached to Na v 1.4 O-glycans are responsible for the additional effect of D1S5-S6 sialic acids on Na v 1.4 gating.…”

Section: Introductionmentioning

confidence: 98%

“…Recently gating of three K v isoforms, K v 2.1, K v 4.2, and K v 4.3, were shown to be modulated by sialic acids attached to O-glycans [13]. None of the three isoforms are N-glycosylated.…”

Section: Introductionmentioning

confidence: 99%

Sialic acids attached to N- and O-glycans within the Nav1.4 D1S5–S6 linker contribute to channel gating

Ednie

Harper

Bennett

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Voltage-gated Na+ channels (Nav) are responsible for the initiation and conduction of neuronal and muscle action potentials. Nav gating can be altered by sialic acids attached to channel N-glycans, typically through isoform-specific electrostatic mechanisms. Methods Using two sets of Chinese Hamster Ovary cell lines with varying abilities to glycosylate glycoproteins, we show for the first time that sialic acids attached to O-glycans and N-glycans within the Nav1.4 D1S5-S6 linker modulate Nav gating. Results All measured steady-state and kinetic parameters were shifted to more depolarized potentials under conditions of essentially no sialylation. When sialylation of only N-glycans or of only O-glycans was prevented, the observed voltage-dependent parameter values were intermediate between those observed under full versus no sialylation. Immunoblot gel shift analyses support the biophysical data. Conclusions The data indicate that sialic acids attached to both N- and O-glycans residing within the Nav1.4 D1S5-S6 linker modulate channel gating through electrostatic mechanisms, with the relative contribution of sialic acids attached to N- versus O-glycans on channel gating being similar. General Significance Protein N- and O-glycosylation can modulate ion channel gating simultaneously. These data also suggest that Nav gating might be altered simply through exposure to different levels of sugar residues that serve as substrates for N- and O-glycosylation. Thus, in disease states that affect sugar substrate levels, the glycosylation process would be impacted, likely resulting in changes in Nav sialylation levels that would lead to modulated channel gating, AP waveforms and conduction.

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Sialic Acids Attached to O-Glycans Modulate Voltage-gated Potassium Channel Gating

Cited by 52 publications

References 65 publications

Reduced Sialylation Impacts Ventricular Repolarization by Modulating Specific K+ Channel Isoforms Distinctly

Reduced Sialylation Impacts Ventricular Repolarization by Modulating Specific K+ Channel Isoforms Distinctly

Physiologic and pathophysiologic consequences of altered sialylation and glycosylation on ion channel function

Sialic acids attached to N- and O-glycans within the Nav1.4 D1S5–S6 linker contribute to channel gating

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