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Depolarization-dependent Induction of Site-specific Changes in Sialylation on N-linked Glycoproteins in Rat Nerve Terminals.

ABSTRACT: Synaptic transmission leading to release of neurotransmitters in the nervous system is a fast and highly dynamic process. Previously, protein interaction and phosphorylation have been thought to be the main regulators of synaptic transmission. Here we show that sialylation of N-linked glycosylation is a novel potential modulator of neurotransmitter release mechanisms by investigating depolarization-dependent changes of formerly sialylated N-linked glycopeptides. We suggest that negatively charged sialic acids can be modulated, similarly to phosphorylation, by the action of sialyltransferases and sialidases thereby changing local structure and function of membrane glycoproteins. We characterized site-specific alteration in sialylation on N-linked glycoproteins in isolated rat nerve terminals after brief depolarization using quantitative sialiomics. We identified 1965 formerly sialylated N-linked glycosites in synaptic proteins and found that the abundances of 430 glycosites changed after 5 s depolarization. We observed changes on essential synaptic proteins such as synaptic vesicle proteins, ion channels and transporters, neurotransmitter receptors and cell adhesion molecules. This study is to our knowledge the first to describe ultra-fast site-specific modulation of the sialiome after brief stimulation of a biological system.

SUBMITTER: Boll I

PROVIDER: S-EPMC8143646 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glycoproteins containing N-linked oligosaccharides were prepared from plasma and liver microsomes of rats aged 0-5 weeks, and galactose and sialic acid content were determined. The sialic acid/galactose ratios in plasma membrane N-glycans remained at about 1 throughout the postnatal period, suggesting that most of the galactose residues are sialylated. In the same way, it was suggested that most of the galactose residues of microsomal N-glycans were sialylated at 0, 4 and 5 weeks of age, but that the degree of sialylation was lower at the other ages, with a minimum at 2 weeks. When the activities of sialyltransferase and galactosyltransferase in liver Golgi membranes were determined, age-dependent changes were found, not only in the specific activities of the enzymes, but also in the Golgi membrane content per g of liver. The activity of galactosyltransferase per g of liver increased immediately after birth, whereas that of sialyltransferase remained at a low level for 2 weeks and then increased to a constant level at 4 weeks. It is probable that this delayed increase in the activity of sialyltransferase results in the decreased sialylation of microsomal N-glycans at 1, 2 and 3 weeks. Sialyltransferase was solubilized from the liver microsomes of rats aged 2, 3 and 4 weeks and characterized. Phosphocellulose column chromatography separated the activity into two subfractions, designated transferase I and transferase II in the order of elution. The increase in total sialyltransferase activity during this period was caused mainly by an increase in transferase I. Rechromatography of each transferase from 3-week-old rats after neuraminidase treatment showed that transferase I but not transferase II contained sialic acid residue(s) and that desialylated transferase I was eluted in a similar way as transferase II. Although the apparent Km value for CMP-N-acetylneuraminic acid and the heat stability of transferase I were different from those of transferase II, the difference was abolished by treating transferase I with neuraminidase, suggesting that transferase II may be a desialylated form of transferase I. These changes in the sialylation of membrane glycoproteins, including sialyltransferase, may be related to the control of liver growth during postnatal development.

Project description:Hypertension is the most prevalent risk factor for cardiovascular disease caused by a persistent increase in arterial blood pressure that has lasting effects on the mechanical properties of affected tissues like myocardium and blood vessels. Our group recently discovered that gut dysbiosis is linked to hypertension in several animal models and humans; however, whether hypertension influences the gut's mechanical properties remains unknown. In this study, we evaluated the hypothesis that hypertension increases fibrosis and thus mechanical properties of the gut. A custom indentation system was used to test colon samples from Wistar Kyoto (WKY) normotensive rats and Spontaneously Hypertensive Rats (SHR). Using force-displacement data, we derived an steady-state modulus metric to quantify mechanical properties of gastrointestinal tissue. We observed that SHR proximal colon has a mean steady-state modulus almost 3 times greater than WKY control rat colon (5.11±1.58kPa and 18.17±11.45kPa, respectively). These increases were associated with increase in vascular smooth muscle cells layer and collagen deposition in the intestinal wall in the SHR.Mechanical characterization of biological materials can provide insight into health and disease of tissue. Recent investigations into a variety of cardiovascular pathologies show coincident changes in the microbiome and pathology of the gut. In this study, we sought to quantify changes in the gut in hypertension through mechanical characterization. Our methods and simple models for characterization, adapted from Hertz indentation models, prove useful to identify a meaningful steady-state modulus metric for small and irregular tissues from laboratory animals. Our data, for the first time, establish a stiffening of the gut wall in Spontaneously Hypertensive Rats. This observation suggests significant structural and functional changes in the gut correlate with hypertension, and future experiments are warranted to explore the specific causal relationship between dysbiosis, fibrosis, and stiffening in the gut during the development and maintenance of hypertension.

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Depolarization-dependent Induction of Site-specific Changes in Sialylation on N-linked Glycoproteins in Rat Nerve Terminals.

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