N-glycosylation in regulation of the nervous system

Abstract

Protein N-glycosylation can influence the nervous system in a variety of ways by affecting functions of glycoproteins involved in nervous system development and physiology. The importance of N-glycans for different aspects of neural development has been well documented. For example, some N-linked carbohydrate structures were found to play key roles in neural cell adhesion and axonal targeting during development. At the same time, the involvement of glycosylation in the regulation of neural physiology remains less understood. Recent studies have implicated N-glycosylation in the regulation of neural transmission, revealing novel roles of glycans in synaptic processes and the control of neural excitability. N-Glycans were found to markedly affect the function of several types of synaptic proteins involved in key steps of synaptic transmission, including neurotransmitter release, reception, and uptake. Glycosylation also regulates a number of channel proteins, such as TRP channels that control responses to environmental stimuli and voltage-gated ion channels, the principal determinants of neuronal excitability. Sialylated carbohydrate structures play a particularly prominent part in the modulation of voltage-gated ion channels. Sialic acids appear to affect channel functions via several mechanisms, including charge interactions, as well as other interactions that probably engage steric effects and interactions with other molecules. Experiments also indicated that some structural features of glycans can be particularly important for their function. Since glycan structures can vary significantly between different cell types and depend on the metabolic state of the cell, it is important to analyze glycan functions using in vivo approaches. While the complexity of the nervous system and intricacies of glycosylation pathways can create serious obstacles for in vivo experiments in vertebrates, recent studies have indicated that more simple and experimentally tractable model organisms like Drosophila should provide important advantages for elucidating evolutionarily conserved functions of N-glycosylation in the nervous system.

Figure 1

Main effects of protein N-glycosylation. N-glycans can potentiate glycoprotein functions by facilitating protein folding and trafficking to the cell surface (a), promoting protein stability on the cell surface via regulation of protein uptake and recycling to the plasma membrane (b), and by enhancing protein activity via changing protein biophysical properties (c). N-Glycosylation is sketched as a single generic N-glycan (not to scale). The number of glycans can be different for distinct proteins, while glycan structures can vary and have different effects on protein functions.

Figure 2

N-Glycosylation can affect neural transmission by modulating voltage-gated ion channels that generate action potentials and determine neuronal excitability, and by influencing synaptic transmission via impact on the function of synaptic proteins, such as synaptic vesicle proteins and neurotransmitter receptors. N-Glycosylation is sketched as a generic N-glycan. Glycans can also include some specific modifications, such as polysialylation and the HNK-1 epitopes (not shown). Modified from (Scott and Panin 2014).

Figure 3

Distribution of the different protein classes among N-glycosylated proteins identified in Drosophila head by glycoproteomics approaches. Figure adapted with permission from (Koles et al. 2007).