Different Pharmacological Properties of GLUT9a and GLUT9b: Potential Implications in Preeclampsia.

Lüscher, Benjamin; Surbek, Daniel; Clemençon, Benjamin; Huang, Xiao; Albrecht, Christiane; Marini, Camilla; Hediger, Matthias; Baumann, Marc (2019). Different Pharmacological Properties of GLUT9a and GLUT9b: Potential Implications in Preeclampsia. Cellular physiology and biochemistry, 53(3), pp. 508-517. Cell Physiol Biochem Press 10.33594/000000154

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BACKGROUND/AIMS Glucose transporter 9 (GLUT9/SLC2A9) is the major regulator of uric acid homeostasis in humans. Hyperuricemia due to impaired regulation by GLUT9 in pregnancy is closely associated with preeclampsia. While GLUT9 is expressed in two alternative splice variants, GLUT9a and GLUT9b, with different subcellular localizations, no functional differences of the two splice variants are known to date. The aim of this study was to investigate the function of both GLUT9 isoforms. METHODS To characterize the different pharmacological properties of GLUT9a and GLUT9b electrophysiological studies of these isoforms and their modified variants, i.e. NmodGLUT9a and NmodGLUT9b, were performed using a Xenopus laevis oocytes model. Currents were measured by an electrode voltage clamp system. RESULTS Functional experiments unveiled that uric acid transport mediated by GLUT9a but not GLUT9b is chloride-dependent: Replacing chloride by different anions resulted in a 3.43±0.63-fold increase of GLUT9a- but not GLUT9b-mediated currents. However, replacement by iodide resulted in a loss of current for GLUT9a but not GLUT9b. Iodide inhibits GLUT9a with an IC50 of 35.1±6.7µM. Modification of the N-terminal domain leads to a shift of the iodide IC50 to 1200±228µM. Using molecular docking studies, we identified two positively charged residues H23 and R31 in the N-terminal domain of hGLUT9a which can explain the observed functional differences. CONCLUSION To the best of our knowledge, this is the first study showing that the N-terminal domain of hGLUT9a has a unique regulatory function and the potential to interact with small negatively charged ions like iodide. These findings may have significant implications in our understanding of hyperuricemia-associated diseases, specifically during pregnancy.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Pränatale Medizin

UniBE Contributor:

Lüscher, Benjamin; Surbek, Daniel; Clemençon, Benjamin; Huang, Xiao; Albrecht, Christiane; Marini, Camilla; Hediger, Matthias and Baumann, Marc

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1421-9778

Publisher:

Cell Physiol Biochem Press

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

26 Sep 2019 09:10

Last Modified:

23 Oct 2019 06:31

Publisher DOI:

10.33594/000000154

PubMed ID:

31502429

Uncontrolled Keywords:

Electrophysiology Glucose transporter type 9 (GLUT9) Iodine Uric acid Uric acid transport

BORIS DOI:

10.7892/boris.133476

URI:

https://boris.unibe.ch/id/eprint/133476

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