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Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT

Author

Listed:
  • Farha Khan

    (University of California, Los Angeles
    Van Andel Institute)

  • Matthias Elgeti

    (University of California, Los Angeles
    Leipzig University Medical School)

  • Samuel Grandfield

    (University of California, Los Angeles
    Renaissance School of Medicine at Stony Brook University)

  • Aviv Paz

    (University of California, Los Angeles
    Hauptman-Woodward Medical Research Institute)

  • Fiona B. Naughton

    (University of California, San Francisco)

  • Frank V. Marcoline

    (University of California, San Francisco)

  • Thorsten Althoff

    (University of California, Los Angeles)

  • Natalia Ermolova

    (University of California, Los Angeles)

  • Ernest M. Wright

    (University of California, Los Angeles)

  • Wayne L. Hubbell

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Michael Grabe

    (University of California, San Francisco)

  • Jeff Abramson

    (University of California, Los Angeles)

Abstract

Sodium-dependent glucose transporters (SGLTs) couple a downhill Na+ ion gradient to actively transport sugars. Here, we investigate the impact of the membrane potential on vSGLT structure and function using sugar uptake assays, double electron-electron resonance (DEER), electrostatic calculations, and kinetic modeling. Negative membrane potentials, as present in all cell types, shift the conformational equilibrium of vSGLT towards an outward-facing conformation, leading to increased sugar transport rates. Electrostatic calculations identify gating charge residues responsible for this conformational shift that when mutated reduce galactose transport and eliminate the response of vSGLT to potential. Based on these findings, we propose a comprehensive framework for sugar transport via vSGLT, where the cellular membrane potential facilitates resetting of the transporter after cargo release. This framework holds significance not only for SGLTs but also for other transporters and channels.

Suggested Citation

  • Farha Khan & Matthias Elgeti & Samuel Grandfield & Aviv Paz & Fiona B. Naughton & Frank V. Marcoline & Thorsten Althoff & Natalia Ermolova & Ernest M. Wright & Wayne L. Hubbell & Michael Grabe & Jeff , 2023. "Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43119-z
    DOI: 10.1038/s41467-023-43119-z
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    References listed on IDEAS

    as
    1. Akira Watanabe & Seungho Choe & Vincent Chaptal & John M. Rosenberg & Ernest M. Wright & Michael Grabe & Jeff Abramson, 2010. "The mechanism of sodium and substrate release from the binding pocket of vSGLT," Nature, Nature, vol. 468(7326), pages 988-991, December.
    2. Lei Han & Qianhui Qu & Deniz Aydin & Ouliana Panova & Michael J. Robertson & Yan Xu & Ron O. Dror & Georgios Skiniotis & Liang Feng, 2022. "Structure and mechanism of the SGLT family of glucose transporters," Nature, Nature, vol. 601(7892), pages 274-279, January.
    3. Yange Niu & Rui Liu & Chengcheng Guan & Yuan Zhang & Zhixing Chen & Stefan Hoerer & Herbert Nar & Lei Chen, 2022. "Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter," Nature, Nature, vol. 601(7892), pages 280-284, January.
    4. David J. Posson & Pinghua Ge & Christopher Miller & Francisco Bezanilla & Paul R. Selvin, 2005. "Small vertical movement of a K+ channel voltage sensor measured with luminescence energy transfer," Nature, Nature, vol. 436(7052), pages 848-851, August.
    5. Weixiao Y. Wahlgren & Elin Dunevall & Rachel A. North & Aviv Paz & Mariafrancesca Scalise & Paola Bisignano & Johan Bengtsson-Palme & Parveen Goyal & Elin Claesson & Rhawnie Caing-Carlsson & Rebecka A, 2018. "Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    6. Paola Bisignano & Chiara Ghezzi & Hyunil Jo & Nicholas F. Polizzi & Thorsten Althoff & Chakrapani Kalyanaraman & Rosmarie Friemann & Matthew P. Jacobson & Ernest M. Wright & Michael Grabe, 2018. "Inhibitor binding mode and allosteric regulation of Na+-glucose symporters," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    7. Wenhao Cui & Yange Niu & Zejian Sun & Rui Liu & Lei Chen, 2023. "Structures of human SGLT in the occluded state reveal conformational changes during sugar transport," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
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