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Review
. 2008 Aug;295(2):E242-53.
doi: 10.1152/ajpendo.90388.2008. Epub 2008 Jun 24.

The facilitative glucose transporter GLUT3: 20 years of distinction

Ian A Simpson  1 , Donard Dwyer, Daniela Malide, Kelle H Moley, Alexander Travis, Susan J Vannucci
Affiliations
Review

The facilitative glucose transporter GLUT3: 20 years of distinction

Ian A Simpson et al. Am J Physiol Endocrinol Metab. 2008 Aug.

Abstract

Glucose metabolism is vital to most mammalian cells, and the passage of glucose across cell membranes is facilitated by a family of integral membrane transporter proteins, the GLUTs. There are currently 14 members of the SLC2 family of GLUTs, several of which have been the focus of this series of reviews. The subject of the present review is GLUT3, which, as implied by its name, was the third glucose transporter to be cloned (Kayano T, Fukumoto H, Eddy RL, Fan YS, Byers MG, Shows TB, Bell GI. J Biol Chem 263: 15245-15248, 1988) and was originally designated as the neuronal GLUT. The overriding question that drove the early work on GLUT3 was why would neurons need a separate glucose transporter isoform? What is it about GLUT3 that specifically suits the needs of the highly metabolic and oxidative neuron with its high glucose demand? More recently, GLUT3 has been studied in other cell types with quite specific requirements for glucose, including sperm, preimplantation embryos, circulating white blood cells, and an array of carcinoma cell lines. The last are sufficiently varied and numerous to warrant a review of their own and will not be discussed here. However, for each of these cases, the same questions apply. Thus, the objective of this review is to discuss the properties and tissue and cellular localization of GLUT3 as well as the features of expression, function, and regulation that distinguish it from the rest of its family and make it uniquely suited as the mediator of glucose delivery to these specific cells.

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Figures

Fig. 1.
Fig. 1.
GLUT3 distribution in rat cerebeller granule cells and human hippocampal neurons. Top left: immunohistochemical distribution of GLUT3 in cerebeller granule cells derived from the cerebellum of 8-day-old rats having undergone differentiation over a subsequent 6 days in culture. Bottom left: corresponding phase micrograph. Right: distribution of GLUT3 in human hippocampal pyramidal neurons. In both human and rat neurons, it is evident that GLUT3 is in axons, dendrites, and cell bodies. Micrographs were previously published (78, 128) and are reprinted here with permission.
Fig. 2.
Fig. 2.
Structural features of GLUT3. Left: model of GLUT3 is oriented with the extracellular face at the top. Loop 1 is depicted in purple, and the membrane-proximal segment of loop 6 is shown in blue. Glucose (CPK rendering) is visible in the pore, and the putative intracellular binding site for forskolin (stick rendering) is indicated. Right: model has been tilted forward 90° to reveal the pore indicated with an asterisk. Small residues that line the pore are shown in green (Gly338, Gly340, and Gly406 and Asn409), and residues where bulkier substitutions may affect pore size are colored yellow (Phe348 and Cys407).
Fig. 3.
Fig. 3.
Murine sperm are highly compartmentalized in terms of structure and function. A: the head and the 2 major pieces of the flagellum, the midpiece, and principal piece. Oxidative respiration is restricted to the midpiece, whereas glycolysis is organized down the length of the principal piece. B: GLUT3 is shown as expressed throughout the flagellum. It is likely that the pentose phosphate pathway is active in the midpiece, which also has high abundance of the germ cell-specific hexokinase, but not other glycolytic enzymes, such as glyceraldehyde-3-phosphate dehydrogenase. Arrowhead points to faint staining in the apical acrosome of one cell to show the location of the head in this sperm. But, as this figure shows, even faint signal in the head is relatively uncommon among murine sperm.
Fig. 4.
Fig. 4.
Preimplantation embryos demonstrate dual immunohistochemical staining for GLUT3 and TUNEL. A: representative wild type (WT); B: heterozygous (Het); C: homozygous knockout (KO) embryo demonstrating GLUT3 (green) and TUNEL (red) along with nuclear ToPro-3 (blue) staining. WT demonstrates apical distribution (arrow); heterozygous embryo demonstrates punctuate distribution of GLUT3 on apical and basolateral surfaces of the trophectoderm (arrowhead); homozygous embryos demonstrate no GLUT3. TUNEL staining progressively increases from WT to homozygous embryos.
Fig. 5.
Fig. 5.
Embryos at 6.5 days in longitudinal sections (E) in situ within maternal deciduas and uterine cavity demonstrate the presence (+/+) (a) consistent with a WT phenotype or absence (b) consistent with a GLUT3-null homozygous phenotype of GLUT3 immunoreaction (arrows) on the embryonic visceral endoderm (EmVe), seen under higher magnification (*) in inset.
Fig. 6.
Fig. 6.
Blastocysts at 6.5 days, fixed in paraformaldehyde and permeabilized with Tween, were incubated with a primary rabbit anti-mouse GLUT3 antibody (A) or a primary murine anti-rat GLUT1 antibody for 1 h at room temperature (B) both at 20 g/ml. GLUT3 is predominantly located in the apical trophectoderm plasma membrane (arrow), whereas GLUT1 is localized to the basolateral surfaces of both the trophectoderm and inner cell mass cells (arrowheads).
Fig. 7.
Fig. 7.
Immunolocalization of GLUT3 in resting and activated neutrophils by confocal microscopy. Phase contrast micrographs (A), corresponding to fluorescence micrographs (B), show the morphology of unstimulated (control) cells: characteristic multinucleated cells with thin cytoplasm. In these cells, GLUT3 (B) exhibits punctate intracellular staining, which appears dispersed throughout the cytoplasm. Phase contrast (C) and corresponding fluorescent images (D) are presented from cells incubated with 100 nM PMA for 10 min. In response to PMA, GLUT3 displays clear redistribution to the cell surface from intracellular locations (D). Intensity of fluorescence at the cell surface remains below that observed over the platelet in the same field (arrow in D). Phase contrast micrographs (E and G) and corresponding fluorescence images (F and H) are presented for cells incubated with bacteria for 20 and 30 min, respectively. Striking morphological changes can be observed during cell activation: cells are larger and have more cytoplasm and large expansions of their plasma membrane; phagocytosed bacteria are seen inside most cells. These morphological changes are accompanied by marked redistribution of GLUT3 immunofluorescence from intracellular locations toward the cell surface, outlining the cell periphery and spike-like plasma membrane projections (E and F). Very bright intracellular spots appear to correspond to phase-dense membrane compartments (arrows in G and H). Platelets (small arrows in G and H) have much lower intensity of fluorescence than observed when activated in D. Bars, 5 μm (D. Malide, I. A. Simpson, and M. Levine, unpublished observations).
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