Developmental regulation of genes mediating murine brain glucose uptake

Abstract

We examined the molecular mechanisms that mediate the developmental increase in murine whole brain 2-deoxyglucose uptake. Northern and Western blot analyses revealed an age-dependent increase in brain GLUT-1 (endothelial cell and glial) and GLUT-3 (neuronal) membrane-spanning facilitative glucose transporter mRNA and protein concentrations. Nuclear run-on experiments revealed that these developmental changes in GLUT-1 and -3 were regulated posttranscriptionally. In contrast, the mRNA and protein levels of the mitochondrially bound glucose phosphorylating hexokinase I enzyme were unaltered. However, hexokinase I enzyme activity increased in an age-dependent manner suggestive of a posttranslational modification that is necessary for enzymatic activation. Together, the postnatal increase in GLUT-1 and -3 concentrations and hexokinase I enzymatic activity led to a parallel increase in murine brain 2-deoxyglucose uptake. Whereas the molecular mechanisms regulating the increase in the three different gene products may vary, the age-dependent increase of all three constituents appears essential for meeting the increasing demand of the maturing brain to fuel the processes of cellular growth, differentiation, and neurotransmission.

The facilitative glucose transporter GLUT3: 20 years of distinction

“…An analysis of GLUT3 protein expression, relative to a series of neuron-specific synaptic proteins such as synaptophysin, SNAP-25, and the ␣3 subunit of Na ϩ -K ϩ -ATPase, demonstrates a strikingly similar pattern in each brain region that correlates with the maturation and regional cerebral glucose utilization (rCGU) profile for each. Thus, it appears that GLUT3 expression in neurons in the rat coincides with maturation and synaptic connectivity (125) and a positive correlation between protein levels of GLUT1, GLUT3, and rCGU was established using immunoautoradiography (30,134) and was also observed in the mouse (64).…”

“…Although expressed in the 8.5-dpc nonneuronal surface ectoderm of the embryo proper, GLUT3 is downregulated significantly by dpc 10.5 (110) and is no longer detectable by dpc 8.5 in fetal brain (64). The consensus of all these studies is 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.…”

Trans-activators Regulating Neuronal Glucose Transporter Isoform-3 Gene Expression in Mammalian Neurons

“…Whereas GLUT 1 is expressed by endothelial cells lining the microvasculature and glial cells, which are components of the blood-brain barrier (10), GLUT 3 is the predominant neuronal isoform (11). We and others have reported previously that although the spatial distribution of GLUT 3 in brain is not age-dependent (12), a temporal distribution exists with low amounts noted during the embryonic/ fetal and early postnatal stages and peak amounts at day 14 -21 (13), which coincides with the timing of synaptogenesis (14 -16). In addition, GLUT 3 localization to the synaptic region and its vesicular trafficking, which involves SNAP-25 and syntaxin-1, proteins of the SNARE complex present in synaptic vesicles, supports a role for GLUT 3 in neurotransmission (17).…”

“…Brain 2-deoxyglucose uptake serves as a surrogate marker for neuronal activity (18); thus GLUT 3, which mediates this glucose uptake, must play a major role in fueling neurotransmission (19). Depolarization of neurons in vitro by the presence of extracellular K ϩ ions or N-methyl-D-aspartate led to an increase in GLUT 3 concentrations, providing credence to this concept (20).Both the processes of neuro-development and depolarization of cultured neurons cause a pre-translational increase in neuronal GLUT 3 expression (13,20). Furthermore, conditions of substrate deficiency such as chronic hypoglycemia or hypoxic ischemia, which depolarize neurons, also pre-translationally increase neuronal GLUT 3 concentrations (21,22).…”

“…Both the processes of neuro-development and depolarization of cultured neurons cause a pre-translational increase in neuronal GLUT 3 expression (13,20). Furthermore, conditions of substrate deficiency such as chronic hypoglycemia or hypoxic ischemia, which depolarize neurons, also pre-translationally increase neuronal GLUT 3 concentrations (21,22).…”