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PNAS 100 (20): 11753-11758

Copyright © 2003 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / PHYSIOLOGY

A glucose sensor hiding in a family of transporters

Ana Díez-Sampedro*, Bruce A. Hirayama*, Christina Osswald{dagger}, Valentin Gorboulev{dagger}, Katharina Baumgarten{dagger}, Christopher Volk{dagger}, Ernest M. Wright*,{ddagger}, and Hermann Koepsell{dagger}

*Department of Physiology, David Geffen School of Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095-1751; and {dagger}Anatomical Institute, University of Wurzburg, Koellikerstrasse 6, 97070 Wurzburg, Germany

Received for publication May 20, 2003.

Abstract: We have examined the expression and function of a previously undescribed human member (SGLT3/SLC5A4) of the sodium/glucose cotransporter gene family (SLC5) that was first identified by the chromosome 22 genome project. The cDNA was cloned and sequenced, confirming that the gene coded for a 659-residue protein with 70% amino acid identity to the human SGLT1. RT-PCR and Western blotting showed that the gene was transcribed and mRNA was translated in human skeletal muscle and small intestine. Immunofluorescence microscopy indicated that in the small intestine the protein was expressed in cholinergic neurons in the submucosal and myenteric plexuses, but not in enterocytes. In skeletal muscle SGLT3 immunoreactivity colocalized with the nicotinic acetylcholine receptor. Functional studies using the Xenopus laevis oocyte expression system showed that hSGLT3 was incapable of sugar transport, even though SGLT3 was efficiently inserted into the plasma membrane. Electrophysiological assays revealed that glucose caused a specific, phlorizin-sensitive, Na+-dependent depolarization of the membrane potential. Uptake assays under voltage clamp showed that the glucose-induced inward currents were not accompanied by glucose transport. We suggest that SGLT3 is not a Na+/glucose cotransporter but instead a glucose sensor in the plasma membrane of cholinergic neurons, skeletal muscle, and other tissues. This points to an unexpected role of glucose and SLC5 proteins in physiology, and highlights the importance of determining the tissue expression and function of new members of gene families.

Key Words: Na/sugar cotransporter • human SGLT3 • muscle

{ddagger} To whom correspondence should be addressed. E-mail: ewright{at}mednet.ucla.edu.

Edited by Michael J. Welsh, University of Iowa College of Medicine, Iowa City, IA, and approved July 2, 2003

This paper was submitted directly (Track II) to the PNAS office.

Abbreviation: αMDG, α-methyl-D-glucopyranoside.

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