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

Abstract

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.

Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

“…The extensive glycosylation and sialylation of voltage gated ion channels is known to modulate channel activity (Tyrrell et al, 2001; Ednie and Bennett, 2012; Baycin-Hizal et al, 2014; Scott and Panin, 2014). Core-glycosylation of Nav1.5 and Nav1.7 does not prevent transport to the cell membrane (Laedermann et al, 2013; Mercier et al, 2015), but core glycosylated Nav1.5 appears to be inactive (Mercier et al, 2015).…”

“…Na v 1.6 from mammalian brain migrates with a MW similar to fully glycosylated Na v 1.2 (Kearney et al, 2002; Wagnon et al, 2015). Glycosylation of the related channels Na v 1.2, Na v 1.4, Na v 1.5 and Na v 1.7 is known to influence protein folding, protease resistance, cell surface localization and channel kinetics (Ednie and Bennett, 2012; Baycin-Hizal et al, 2014; Lazniewska and Weiss, 2014). Core-glycosylated Na v 1.5 and Na v 1.7 can reach the surface of transfected HEK cells but may lack channel activity (Laedermann et al, 2013; Mercier et al, 2015).…”

Modulation of Cav3.2 T-type calcium channel permeability by asparagine-linked glycosylation

“…Our observation that the conducting properties of hCa v 3.2 channels can be altered by the amount of occupied N-glycosylation sites in the protein may have important pathophysiological implications, as a defect in ion channel glycosylation has been reported in numerous disease states. 38 Interestingly, a causal increased activity of T-type channels has been documented in various animal models of chronic pain 11,39,40 including painful diabetic neuropathy. 41 And consistent with the idea that the increased T-type channel activity may be caused by a defect in the glycosylation of the channel, in vivo desialylation by injection of neuraminidase in an animal model of diabetes restored normal T-type currents and pain behavior.…”

Neurological Aspects of Human Glycosylation Disorders

“…Also, tightly regulated activation/deactivation of voltage-gated ion-channels in the cell membrane of excitable cells, including neurons, is vital for their proper function. Most of these channel proteins contain sialyated N-glycans, which are often vital for their proper function (Baycin-Hizal et al 2014, Johnson & Bennett 2008). Lack of N-glycans can cause improper folding and transport of the proteins but changes in sialylation give a shifted gating in the depolarized direction (Johnson & Bennett 2008).…”