Regulation of GLUT4 activity in myotubes by 3-O-methyl-D-glucose

Ofer Shamni, Guy Cohen, Arie Gruzman, Hilal Zaid, Amira Klip, Erol Cerasi, Shlomo Sasson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The rate of glucose influx to skeletal muscles is determined primarily by the number of functional units of glucose transporter-4 (GLUT4) in the myotube plasma membrane. The abundance of GLUT4 in the plasma membrane is tightly regulated by insulin or contractile activity, which employ distinct pathways to translocate GLUT4-rich vesicles from intracellular compartments. Various studies have indicated that GLUT4 intrinsic activity is also regulated by conformational changes and/or interactions with membrane components and intracellular proteins in the vicinity of the plasma membrane. Here we show that the non-metabolizable glucose analog 3-O-methyl-D-glucose (MeGlc) augmented the rate of hexose transport into myotubes by increasing GLUT4 intrinsic activity without altering the content of the transporter in the plasma membrane. This effect was not a consequence of ATP depletion or hyperosmolar stress and did not involve Akt/PKB or AMPK signal transduction pathways. MeGlc reduced the inhibitory potency (increased Ki) of indinavir, a selective inhibitor of GLUT4, in a dose-dependent manner. Kinetic analyses indicate that MeGlc induced changes in GLUT4 or GLUT4 complexes within the plasma membrane, which enhanced the hexose transport activity and reduced the potency of indinavir inhibition. Finally, we present a simple kinetic analysis for screening and discovering low molecular weight compounds that augment GLUT4 activity.

Original languageEnglish
Pages (from-to)1900-1910
Number of pages11
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1859
Issue number10
DOIs
StatePublished - Oct 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier B.V.

Funding

The authors would like to acknowledge support from the Hebrew University Applied Research Fund A (2011), the Baby Seed Fund of the Yissum Research Development Company of the Hebrew University of Jerusalem (2011), and the Alex Grass Center for Drug Design and Synthesis at the Hebrew University (2013). O.S. and G.C. received fellowships from the Hebrew University Center for Diabetes Research.

FundersFunder number
Hebrew University Center for Diabetes Research
Yissum Research Development Company of the Hebrew University of Jerusalem
Hebrew University of Jerusalem

    Keywords

    • Glucose transport
    • Glucose transporter type-4 (GLUT4)
    • HIV-protease inhibitor
    • Intrinsic activity
    • Kinetics
    • Skeletal muscle

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