Disruption of asparagine-linked glycosylation to rescue and alter gating of the NaV1.5-Na+ channel

Wang, Pu; Zhu, Xiufang; Wei, Mengyan; Liu, Yangong; Yoshimura, Kenshi; Zheng, Mingqi; Liu, Gang; Kume, Shinichiro; Kurokawa, Tetsuji; Ono, Katsushige

doi:10.1007/s00380-020-01736-4

Cited by 3 publications

(1 citation statement)

References 30 publications

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“…Glycosylation of Nav channels has been implicated in altering biophysical properties, such as gating, trafficking, and localization (Zhang et al, 1999; Cortada et al, 2019; Ednie and Bennett, 2012; Wang et al, 2021). Although several studies have outlined the effects of differing composition and amounts of glycosylation in vitro and in vivo , little work has been conducted regarding the structural effect of N-linked glycans on Nav channels and their impact on interactions between the channels and accessory β-subunits.…”

Section: Discussionmentioning

confidence: 99%

Isoform-specific N-linked glycosylation of voltage-gated sodium channel alpha-subunits alters beta-subunit binding sites

Beaudoin,

Kohli,

Salvage

et al. 2024

Preprint

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Voltage-gated sodium channel beta-subunits (Nav1.1-1.9) initiate and propagate action potentials in neurons and myocytes. The Nav beta-subunits (beta1-4) have been shown to modulate beta-subunit properties. Homo-oligomerization of beta-subunits on neighboring or opposing plasma membranes has been suggested to facilitate cis or trans interactions, respectively. The interactions between several Nav channel isoforms and beta-subunits have been determined using cryogenic electron microscopy (cryo-EM). Interestingly, the Nav cryo-EM structures reveal the presence of N-linked glycosylation sites. However, only the first glycan moieties are typically resolved at each site due to the flexibility of mature glycan trees. Thus, existing cryo-EM structures may risk de-emphasizing the structural implications of glycans on the Nav channels. Herein, molecular modelling and all-atom molecular dynamics simulations were applied to investigate the conformational landscape of N-linked glycans on Nav channel surfaces. The simulations revealed that negatively-charged sialic acid residues of two glycan sites may interact with voltage-sensing domains. Notably, two Nav1.5 isoform-specific glycans extensively cover the alpha-subunit region that, in other Nav channel alpha-subunit isoforms, corresponds to the binding site for the beta1- (and likely beta3-) subunit immunoglobulin (Ig) domain. Nav1.8 contains a unique N-linked glycosylation site that likely prevents its interaction with the beta2 and beta4-subunit Ig domain. These isoform-specific glycans may have evolved to facilitate specific functional interactions, for example by redirecting beta-subunit Ig-domains outwards to permit cis or trans supra-clustering within specialized cellular compartments such as the cardiomyocyte perinexal space. Further experimental work is necessary to validate these predictions.

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Section: Discussionmentioning

confidence: 99%

Isoform-specific N-linked glycosylation of voltage-gated sodium channel alpha-subunits alters beta-subunit binding sites

Beaudoin,

Kohli,

Salvage

et al. 2024

Preprint

View full text Add to dashboard Cite

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Serum microRNA-30d is a sensitive biomarker for angiotensin II-induced cardiovascular complications in rats

Miyamoto

Ono

2021

Heart Vessels

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Isoform-specific N-linked glycosylation of NaV channel α-subunits alters β-subunit binding sites

Beaudoin,

Kohli,

Salvage

et al. 2024

Journal of General Physiology

View full text Add to dashboard Cite

Voltage-gated sodium channel α-subunits (NaV1.1–1.9) initiate and propagate action potentials in neurons and myocytes. The NaV β-subunits (β1–4) have been shown to modulate α-subunit properties. Homo-oligomerization of β-subunits on neighboring or opposing plasma membranes has been suggested to facilitate cis or trans interactions, respectively. The interactions between several NaV channel isoforms and β-subunits have been determined using cryogenic electron microscopy (cryo-EM). Interestingly, the NaV cryo-EM structures reveal the presence of N-linked glycosylation sites. However, only the first glycan moieties are typically resolved at each site due to the flexibility of mature glycan trees. Thus, existing cryo-EM structures may risk de-emphasizing the structural implications of glycans on the NaV channels. Herein, molecular modeling and all-atom molecular dynamics simulations were applied to investigate the conformational landscape of N-linked glycans on NaV channel surfaces. The simulations revealed that negatively charged sialic acid residues of two glycan sites may interact with voltage-sensing domains. Notably, two NaV1.5 isoform-specific glycans extensively cover the α-subunit region that, in other NaV channel α-subunit isoforms, corresponds to the binding site for the β1- (and likely β3-) subunit immunoglobulin (Ig) domain. NaV1.8 contains a unique N-linked glycosylation site that likely prevents its interaction with the β2 and β4-subunit Ig-domain. These isoform-specific glycans may have evolved to facilitate specific functional interactions, for example, by redirecting β-subunit Ig-domains outward to permit cis or trans supraclustering within specialized cellular compartments such as the cardiomyocyte perinexal space. Further experimental work is necessary to validate these predictions.

show abstract

Disruption of asparagine-linked glycosylation to rescue and alter gating of the NaV1.5-Na+ channel

Cited by 3 publications

References 30 publications

Isoform-specific N-linked glycosylation of voltage-gated sodium channel alpha-subunits alters beta-subunit binding sites

Isoform-specific N-linked glycosylation of voltage-gated sodium channel alpha-subunits alters beta-subunit binding sites

Serum microRNA-30d is a sensitive biomarker for angiotensin II-induced cardiovascular complications in rats

Isoform-specific N-linked glycosylation of NaV channel α-subunits alters β-subunit binding sites

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