Modulation of Voltage‐Gated Ion Channels by Sialylation

Abstract

Control and modulation of electrical signaling is vital to normal physiology, particularly in neurons, cardiac myocytes, and skeletal muscle. The orchestrated activities of variable sets of ion channels and transporters, including voltage‐gated ion channels (VGICs), are responsible for initiation, conduction, and termination of the action potential (AP) in excitable cells. Slight changes in VGIC activity can lead to severe pathologies including arrhythmias, epilepsies, and paralyses, while normal excitability depends on the precise tuning of the AP waveform. VGICs are heavily posttranslationally modified, with upward of 30% of the mature channel mass consisting of N‐ and O‐glycans. These glycans are terminated typically by negatively charged sialic acid residues that modulate voltage‐dependent channel gating directly. The data indicate that sialic acids alter VGIC activity in isoform‐specific manners, dependent in part, on the number/location of channel sialic acids attached to the pore‐forming alpha and/or auxiliary subunits that often act through saturating electrostatic mechanisms. Additionally, cell‐specific regulation of sialylation can affect VGIC gating distinctly. Thus, channel sialylation is likely regulated through two mechanisms that together contribute to a dynamic spectrum of possible gating motifs: a subunit‐specific mechanism and regulated (aberrant) changes in the ability of the cell to glycosylate. Recent studies showed that neuronal and cardiac excitability is modulated through regulated changes in voltage‐gated Na + channel sialylation, suggesting that both mechanisms of differential VGIC sialylation contribute to electrical signaling in the brain and heart. Together, the data provide insight into an important and novel paradigm involved in the control and modulation of electrical signaling. © 2012 American Physiological Society. Compr Physiol 2:1269‐1301, 2012.

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

“…[28][29][30] To assess the role of N-glycosylation in T-type channel function, we used Nglycosylation-deficient hCa v 3.2 channels where glycosylation motifs have been disrupted by mutagenesis. It was previously proposed that sialic acid residues attached to the outermost ends of glycan chains may contribute to the negative surface potential, and contributing to the gating modulation of some voltagegated Na C and K C channels by an electrostatic mechanism.…”

Insufficiency of Cellular Energy (ICE) May Precede Neurodegeneration in Alzheimer’s Disease and Be Treatable via the Alternative Cellular Energy (ACE) Pathway

“…These channels are heavily glycosylated molecules and, therefore, cannot be readily brought back into the cell for recycling. If activation increases their turnover, then cellular energy will be required to maintain adequate numbers of ion channels within the external cell membrane [32]. The loss of ion channels would reduce ACE pathway input.…”

Systemic Blockade of Sialylation in Mice with a Global Inhibitor of Sialyltransferases

“…Synthesis of 2,4,7,8,9-Pentaacetyl-3F ax -Neu5Ac-CO 2 Me (3F-NeuAc)-Methyl 5-acetetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-D-galactonon-2-enonate (23.8 g, 50.3 mmol, 1 eq) was dissolved in nitromethane (197 ml), and H 2 O (33 ml) was added. Select-Fluor (71.3 g, 201.2 mmol, 4 eq) was added, and the reaction was left to vigorously stir for 2 days at room temperature.…”

“…For example, as ligands for sialic acid binding proteins, sialosides mediate cellular homing and adhesion of leukocytes (3), modulation of immune responses (4), and adhesion of viral and bacterial pathogens to host cells (5). Sialosides also play key roles in fertilization (6), brain development (7), muscular function (8), and kidney function (9). Genetic deficiency in the cellular biosynthesis of sialic acid results in lethality during embryonic development in mice (10), highlighting the importance of sialic acid at the organismal level.…”