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

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 () and Jeff Abramson ()
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Farha Khan: University of California, Los Angeles
Matthias Elgeti: University of California, Los Angeles
Samuel Grandfield: University of California, Los Angeles
Aviv Paz: University of California, Los Angeles
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
Michael Grabe: University of California, San Francisco
Jeff Abramson: University of California, Los Angeles

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43119-z

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