title: GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake.
abstract: Serotonin (5-HT) transporter (SERT) regulates the level of 5-HT in placenta. Initially, we found that in gestational diabetes mellitus (GDM), whereas free plasma 5-HT levels were elevated, the 5-HT uptake rates of trophoblast were significantly down-regulated, due to impairment in the translocation of SERT molecules to the cell surface. We sought to determine the factors mediating the down-regulation of SERT in GDM trophoblast. We previously reported that an endoplasmic reticulum chaperone, ERp44, binds to Cys200 and Cys209 residues of SERT to build a disulfide bond. Following this posttranslational modification, before trafficking to the plasma membrane, SERT must be dissociated from ERp44; and this process is facilitated by insulin signaling and reversed by the insulin receptor blocker AGL2263. However, the GDM-associated defect in insulin signaling hampers the dissociation of ERp44 from SERT. Furthermore, whereas ERp44 constitutively occupies Cys200/Cys209 residues, one of the SERT glycosylation sites, Asp208 located between the two Cys residues, cannot undergo proper glycosylation, which plays an important role in the uptake efficiency of SERT. Herein, we show that the decrease in 5-HT uptake rates of GDM trophoblast is the consequence of defective insulin signaling, which entraps SERT with ERp44 and impairs its glycosylation. In this regard, restoring the normal expression of SERT on the trophoblast surface may represent a novel approach to alleviating some GDM-associated complications.
authors.affiliation: Departments of Biochemistry and Molecular Biology and.
authors.forename: Yicong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Biochemistry and Molecular Biology and.
authors.forename: Coedy
authors.initials: C
authors.lastname: Hadden
authors.affiliation: Departments of Biochemistry and Molecular Biology and.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singh
authors.affiliation: Departments of Biochemistry and Molecular Biology and.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Mercado
authors.affiliation: Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205;
authors.forename: Pamela
authors.initials: P
authors.lastname: Murphy
authors.affiliation: Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205;
authors.forename: Nafisa K
authors.initials: NK
authors.lastname: Dajani
authors.affiliation: Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205;
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Lowery
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114; and.
authors.forename: Drucilla J
authors.initials: DJ
authors.lastname: Roberts
authors.affiliation: INSERM UMR S-839, Institut du Fer a Moulin, 75005 Paris, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
authors.affiliation: Departments of Biochemistry and Molecular Biology and kilicfusun@UAMS.edu.
authors.forename: Fusun
authors.initials: F
authors.lastname: Kilic
mesh_terms: D000293:Adolescent; D000328:Adult; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006031:Glycosylation; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis*; D018832:Molecular Chaperones / Q000096:biosynthesis*; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis*; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology
chemical_list: C451899:ERP44 protein, human; D007328:Insulin; D008565:Membrane Proteins; D018832:Molecular Chaperones; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin
keywords: ERp44; gestational diabetes mellitus; insulin; serotonin; serotonin transporter