A glucose sensor hiding in a family of transporters

Abstract

We have examined the expression and function of a previously undescribed human member (SGLT3͞SLC5A4) of the sodium͞glu-cose 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.Na͞sugar cotransporter ͉ human SGLT3 ͉ muscle

Analysis of Transport Activity of Arabidopsis Sugar Alcohol Permease Homolog AtPLT5

“…Specific transporters within the MFS have been demonstrated to function as sensors, for example, on binding glucose, human SGLT3 forms a Na ϩ -permeable channel and conducts Na ϩ but not glucose (19). To determine whether the ion currents observed in oocytes when AtPLT5 was expressed were coupled to substrate uptake, 14 C-labeled glucose, sorbitol, sucrose, or maltose were applied externally to oocytes.…”

Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects

“…For example, GPR40 and GPR119 are both GPCR that may stimulate incretin release in response to fatty acids, and agonists of these receptors could be therapeutically useful in diabetes (8). Furthermore, sweet taste sensors other than T1R2, such as SGLT3 (11), could be important in the detecting carbohydrate in the small intestine.…”

Na+, Cl−, and pH Dependence of the Human Choline Transporter (hCHT) inXenopusOocytes: The Proton Inactivation Hypothesis of hCHT in Synaptic Vesicles

“…Other members of the SLC5 family to which CHT belongs exhibit tight coupling and fixed stoichiometry, e.g., two Na ϩ ions per substrate molecule (Eskandari et al, 1997;Loo et al, 2000;Prasad and Ganapathy, 2000;DiezSampedro et al, 2001;. However, hSGLT3, also a member of the SLC5 family, is described as a glucose-gated ion channel (Diez-Sampedro et al, 2003), suggesting functional diversity of the SLC5 family . Whether the extra charge contributes to coupled transport is unknown, and slippage occurs alongside choline transport, as has been generally proposed for a host of transporters (Nelson et al, 2002).…”