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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.

SUBMITTER: Scott H

PROVIDER: S-EPMC3976283 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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The role of protein N-glycosylation in neural transmission.

Scott Hilary H Panin Vladislav M VM

Glycobiology 20140318 5

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, tra ...[more]

PMID: 24643084

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Project description:Water forms the basis of lubrication in the human body, but is unable to provide sufficient lubrication without additives. The importance of biolubrication becomes evident upon aging and disease, particularly under conditions that affect secretion or composition of body fluids. Insufficient biolubrication, may impede proper speech, mastication and swallowing, underlie excessive friction and wear of articulating cartilage surfaces in hips and knees, cause vaginal dryness, and result in dry, irritated eyes. Currently, our understanding of biolubrication is insufficient to design effective therapeutics to restore biolubrication. Aim of this study was to establish the role of structure and glycosylation of adsorbed protein films in biolubrication, taking the oral cavity as a model and making use of its dynamics with daily perturbations due to different glandular secretions, speech, drinking and eating, and tooth brushing. Using different surface analytical techniques (a quartz crystal microbalance with dissipation monitoring, colloidal probe atomic force microscopy, contact angle measurements and X-ray photo-electron spectroscopy), we demonstrated that adsorbed salivary conditioning films in vitro are more lubricious when their hydrophilicity and degree of glycosylation increase, meanwhile decreasing their structural softness. High-molecular-weight, glycosylated proteins adsorbing in loops and trains, are described as necessary scaffolds impeding removal of water during loading of articulating surfaces. Comparing in vitro and in vivo water contact angles measured intra-orally, these findings were extrapolated to the in vivo situation. Accordingly, lubricating properties of teeth, as perceived in 20 volunteers comprising of equal numbers of male and female subjects, could be related with structural softness and glycosylation of adsorbed protein films on tooth surfaces. Summarizing, biolubrication is due to a combination of structure and glycosylation of adsorbed protein films, providing an important clue to design effective therapeutics to restore biolubrication in patients with insufficient biolubrication.

Project description:Glycosylation is a frequent and heterogeneous posttranslational protein modification occurring in all domains of life. While protein N-glycosylation at asparagine and O-glycosylation at serine, threonine or hydroxyproline residues have been studied in great detail, only few data are available on O-glycosidic attachment of glycans to the amino acid tyrosine. In this study, we describe the identification and characterization of a bacterial protein tyrosine O-glycosylation system. In the Gram-positive, mesophilic bacterium Paenibacillus alvei CCM 2051(T), a polysaccharide consisting of [-->3)-beta-d-Galp-(1[alpha-d-Glcp-(1-->6)] -->4)-beta-d-ManpNAc-(1-->] repeating units is O-glycosidically linked via an adaptor with the structure -[GroA-2-->OPO(2)-->4-beta-d-ManpNAc-(1-->4)] -->3)-alpha-l-Rhap-(1-->3)-alpha-l-Rhap-(1-->3)-alpha-l-Rhap-(1-->3)-beta-d-Galp-(1--> to specific tyrosine residues of the S-layer protein SpaA. A +AH4-24.3-kb S-layer glycosylation (slg) gene cluster encodes the information necessary for the biosynthesis of this glycan chain within 18 open reading frames (ORF). The corresponding translation products are involved in the biosynthesis of nucleotide-activated monosaccharides, assembly and export as well as in the transfer of the completed polysaccharide chain to the S-layer target protein. All ORFs of the cluster, except those encoding the nucleotide sugar biosynthesis enzymes and the ATP binding cassette (ABC) transporter integral transmembrane proteins, were disrupted by the insertion of the mobile group II intron Ll.LtrB, and S-layer glycoproteins produced in mutant backgrounds were analyzed by mass spectrometry. There is evidence that the glycan chain is synthesized in a process comparable to the ABC-transporter-dependent pathway of the lipopolysaccharide O-polysaccharide biosynthesis. Furthermore, with the protein WsfB, we have identified an O-oligosaccharyl:protein transferase required for the formation of the covalent beta-d-Gal-->Tyr linkage between the glycan chain and the S-layer protein.

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The role of protein N-glycosylation in neural transmission.

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The role of protein N-glycosylation in neural transmission.

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