A serotonin-induced N-glycan switch regulates platelet aggregation.
Serotonin (5-HT) is a multifunctional signaling molecule that plays different roles in a concentration-dependent manner. We demonstrated that elevated levels of plasma 5-HT accelerate platelet aggregation resulting in a hypercoagulable state in which the platelet surface becomes occupied by several glycoproteins. Here we study the novel hypothesis that an elevated level of plasma 5-HT results in modification of the content of N-glycans on the platelet surface and this abnormality is associated with platelet aggregation. Mass spectrometry of total surface glycoproteins on platelets isolated from wild-type mice infused for 24 hours with saline or 5-HT revealed that the content of glycoproteins on platelets from 5-HT-infused mice switched from predominantly N-acetyl-neuraminic acid (Neu5Ac) to N-glycolyl-neuraminic acid (Neu5Gc). Cytidine monophosphate-N-acetylneuraminate hydroxylase (CMAH) synthesizes Neu5Gc from Neu5Ac. Up-regulation of Neu5Gc content on the platelet surface resulted from an increase in the catalytic function, not expression, of CMAH in platelets of 5-HT-infused mice. The highest level of Neu5Gc was observed in platelets of 5-HT-infused, 5-HT transporter-knock out mice, suggesting that the surface delineated 5-HT receptor on platelets may promote CMAH catalytic activity. These new findings link elevated levels of plasma 5-HT to altered platelet N-glycan content, a previously unrecognized abnormality that may favor platelet aggregation.
Departments of Biochemistry and Molecular Biology, and Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Charles P
CP
Mercado
Maritza V
MV
Quintero
Yicong
Y
Li
Preeti
P
Singh
Alicia K
AK
Byrd
Krajang
K
Talabnin
Mayumi
M
Ishihara
Parastoo
P
Azadi
Nancy J
NJ
Rusch
Balagurunathan
B
Kuberan
Luc
L
Maroteaux
Fusun
F
Kilic
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005591:Chemical Fractionation; D002853:Chromatography, Liquid; D005434:Flow Cytometry; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000097:blood / Q000235:genetics; D019158:N-Acetylneuraminic Acid / Q000737:chemistry / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*
D015415:Biomarkers; D011134:Polysaccharides; D012701:Serotonin; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase; D019158:N-Acetylneuraminic Acid