The role of protein N-glycosylation in neural transmission

Abstract

Recent studies have explored the function of N-linked glycosylation in the nervous system, demonstrating essential roles of carbohydrate structures in neural development. The function of N-glycans in neural physiology remains less understood; however, increasing evidence indicates that N-glycans can play specific modulatory roles controlling neural transmission and excitability of neural circuits. These roles are mediated via effects on synaptic proteins involved in neurotransmitter release, transporters that regulate nerotransmitter concentrations, neurotransmitter receptors, as well as via regulation of proteins that control excitability and response to milieu stimuli, such as voltage-gated ion channels and transient receptor potential channels, respectively. Sialylated N-glycan structures are among the most potent modulators of cell excitability, exerting prominent effects on voltage gated Na(+) and K(+) channels. This modulation appears to be underlain by complex molecular mechanisms involving electrostatic effects, as well as interaction modes based on more specific steric effects and interactions with lectins and other molecules. Data also indicate that particular features of N-glycans, such as their location on a protein and structural characteristics, can be specifically associated with the effect of glycosylation. These features and their functional implications can vary between different cell types, which highlight the importance of in vivo analyses of glycan functions. Experimental challenges are associated with the overwhelming complexity of the nervous system and glycosylation pathways in vertebrates, and thus model organisms like Drosophila should help elucidate evolutionarily conserved mechanisms underlying glycan functions. Recent studies supported this notion and shed light on functions of several glycosylation genes involved in the regulation of the nervous system.

Keywords: Drosophila; glycosylation; ion channels; neural transmission; sialylation.

Fig. 1.

N-glycosylation can regulate neural transmission by modulating voltage-gated ion channels that generate action potential on neuronal membranes, and by affecting synaptic transmission via impact on the function of synaptic vesicle proteins and postsynaptic neurotransmitter receptors. N-glycosylation is sketched as a single generic N-glycan (not to scale), while the number of modifications sites can be different for distinct proteins, and particular glycan structures can significantly vary and include some specific modifications, such as polysialylation and the HNK-1 epitopes (not shown).