Glutamate Mediates Acute Glucose Transport Inhibition in Hippocampal Neurons

Abstract

Although it is known that brain activity is fueled by glucose, the identity of the cell type that preferentially metabolizes the sugar remains elusive. To address this question, glucose uptake was studied simultaneously in cultured hippocampal neurons and neighboring astrocytes using a real-time assay based on confocal epifluorescence microscopy and fluorescent glucose analogs. Glutamate, although stimulating glucose transport in astrocytes, strongly inhibited glucose transport in neurons, producing in few seconds a 12-fold increase in the ratio of astrocytic-to-neuronal uptake rate. Neuronal transport inhibition was reversible on removal of the neurotransmitter and displayed an IC 50 of 5 M, suggesting its occurrence at physiological glutamate concentrations. The phenomenon was abolished by CNQX and mimicked by AMPA, demonstrating a role for the cognate subset of ionotropic glutamate receptors. Transport inhibition required extracellular sodium and calcium and was mimicked by veratridine but not by membrane depolarization with high K ϩ or by calcium overloading with ionomycin. Therefore, glutamate inhibits glucose transport via AMPA receptor-mediated sodium entry, whereas calcium entry plays a permissive role. This phenomenon suggests that glutamate redistributes glucose toward astrocytes and away from neurons and represents a novel molecular mechanism that may be important for functional imaging of the brain using positron emission tomography.

GSM Mobile Phone Radiation Suppresses Brain Glucose Metabolism

“…Therefore, GSM phone radiation can have a direct influence on the two processes or an indirect influence through modulation of neuronal activity. To our knowledge, there have been no investigations on the effects of GSM radiation on glucose transporter proteins, or glutamate-based modulation of glucose transporter activity in neurons and astrocytes (Loaiza et al, 2003;Porras et al, 2004). Although there are some data showing that GSM field can modulate activity or expression of various enzyme proteins (Moustafa et al, 2001;Ammari et al, 2008;Vanderstraeten and Verschaeve, 2008), we are not aware of any similar studies on the hexokinase and glucose-6-phosphatase that are responsible for FDG phosphorylation and FDG-6P hydrolysis, the k3 and k4 constants in the [ 18 F]-FDG kinetic model (Phelps et al, 1979), respectively.…”

Brain Lactate Metabolism: The Discoveries and the Controversies

“…Glutamate inhibits NBDG transport into cultured neurons (Porras et al, 2004; Table 3) and stimulates glucose transport into cultured astrocytes (Loaiza et al, 2003; Table 1). These findings have been interpreted by Pierre et al (2009) as rerouting of glucose from neurons to astrocytes during glutamatergic neurotransmission, so neurons would depend on astrocyte-derived lactate as a fuel, in accordance with the astrocyte-neuron lactate shuttle hypothesis.…”

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

“…If the observed 7.4-fold increase in GLUT1 k cat for net glucose import between 241C and 371C (Lowe and Walmsley, 1986) is also observed with GLUT3, then k cat for GLUT1 and GLUT3 at 371C are 1,116 and 6,512/sec, respectively (see Table 1). Interestingly, recent tissue culture studies of Barros and colleagues used the glucose analogs [2-[N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino]-2-deoxyglucose (2NBDG) and 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-6-deoxyglucose (6NBDG), which are transported very slowly, to show that glutamate can reciprocally inhibit glucose uptake in neurons while promoting transport in astrocytes; the mechanism(s) by which these modulations are achieved, that is alterations in k cat or K m , and confirmation that they occur in vivo remain to be established (Loaiza et al, 2003;Porras et al, 2004). Although the fluorescent sugars are generally considered to be very poor substrates for GLUT1 (Cloherty et al, 1995), the authors show that NBDG transport is inhibited by the glucose transport inhibitor CB.…”