Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: An immunohistochemical study

Chiry, Oriana; Fishbein, William N.; Merezhinskaya, Natalya; Clarke, Stéphanie; Galuske, Ralf A. W.; Magistretti, Pierre J.; Pellerin, Luc

doi:10.1016/j.brainres.2008.06.025

Cited by 26 publications

(21 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MCT2 is the main monocarboxylate transporter isoform present on neurons [20,30,40]. In MCT2 rats, no rise in lactate content was observed during whisker stimulation.…”

Section: Discussionmentioning

confidence: 99%

A neuronal MCT2 knockdown in the rat somatosensory cortex reduces both the NMR lactate signal and the BOLD response during whisker stimulation

Mazuel

Blanc

Repond³

et al. 2017

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Although several in vitro and ex vivo evidence support the existence of lactate exchange between astrocytes and neurons, a direct demonstration in vivo is still lacking. In the present study, a lentiviral vector carrying a short hairpin RNA (shRNA) was used to downregulate the expression of the monocarboxylate transporter type 2 (MCT2) in neurons of the rat somatosensory cortex (called S1BF) by ~ 25%. After one hour of whisker stimulation, HRMAS 1H-NMR spectroscopy analysis of S1BF perchloric acid extracts showed that while an increase in lactate content is observed in both uninjected and shRNA-control injected extracts, such an effect was abrogated in shMCT2 injected rats. A 13C-incorporation analysis following [1-13C]glucose infusion during the stimulation confirmed that the elevated lactate observed during activation originates from newly synthesized [3-13C]lactate, with blood-derived [1-13C]glucose being the precursor. Moreover, the analysis of the 13C-labeling of glutamate in position C3 and C4 indicates that upon activation, there is an increase in TCA cycle velocity for control rats while a decrease is observed for MCT2 knockdown animals. Using in vivo localized 1H-NMR spectroscopy, an increase in lactate levels is observed in the S1BF area upon whisker stimulation for shRNA-control injected rats but not for MCT2 knockdown animals. Finally, while a robust BOLD fMRI response was evidenced in control rats, it was absent in MCT2 knockdown rats. These data not only demonstrate that glucose-derived lactate is locally produced following neuronal activation but also suggest that its use by neurons via MCT2 is probably essential to maintain synaptic activity within the barrel cortex.

show abstract

“…MCT2 is the main monocarboxylate transporter isoform present on neurons [20,30,40]. In MCT2 rats, no rise in lactate content was observed during whisker stimulation.…”

Section: Discussionmentioning

confidence: 99%

A neuronal MCT2 knockdown in the rat somatosensory cortex reduces both the NMR lactate signal and the BOLD response during whisker stimulation

Mazuel

Blanc

Repond³

et al. 2017

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…52,53 MCT3 has an intermediate affinity (Km 6 mmol/L) 54 and is predominantly expressed in retinal epithelial cells and in the choroid plexus epithelial cells (which are developmentally homologous to the latter), but not in the ependymal cells lining the cerebral ventricles. 17 The high-affinity transporter MCT2 is abundantly detected on neurons and astrocytes by immunohistochemical methods, 55 but shows substantial species differences in distribution. In rat brain, MCT2 immunoreactivity has primarily been found on perivascular endfeet 8,9,56 and postsynaptic densities.…”

Section: Monocarboxylate Transportersmentioning

confidence: 99%

Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

Bergersen

2014

J Cereb Blood Flow Metab

189

166

View full text Add to dashboard Cite

Lactate acts as a 'buffer' between glycolysis and oxidative metabolism. In addition to being exchanged as a fuel by the monocarboxylate transporters (MCTs) between cells and tissues with different glycolytic and oxidative rates, lactate may be a 'volume transmitter' of brain signals. According to some, lactate is a preferred fuel for brain metabolism. Immediately after brain activation, the rate of glycolysis exceeds oxidation, leading to net production of lactate. At physical rest, there is a net efflux of lactate from the brain into the blood stream. But when blood lactate levels rise, such as in physical exercise, there is net influx of lactate from blood to brain, where the lactate is used for energy production and myelin formation. Lactate binds to the lactate receptor GPR81 aka hydroxycarboxylic acid receptor (HCAR1) on brain cells and cerebral blood vessels, and regulates the levels of cAMP. The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain constitute the focus of this review. They are possible targets for new therapeutic drugs and interventions. The author proposes that lactate actions in the brain through MCTs and the lactate receptor underlie part of the favorable effects on the brain resulting from physical exercise.

show abstract

“…Although 14 isoforms of MCTs have been identified by in silico analysis of the human genome (known as the SLC16A membrane transporter family), only 4 (MCTs 1-4) are known to be involved in lactic acid transport in normal and tumor tissue [17], [18], [19]. We [10] and others [20], [21], [22], [23] have previously demonstrated differential expression of MCT isoforms in brain tumors versus normal brain. In vitro and in vivo studies by us and others have used RNA interference and α-cyano-4-hydroxycinnamic acid (ACCA, CHC), a small-molecule inhibitor against MCTs, to target tumor expressed MCT isoforms and selectively interfere with lactate efflux by glioma [8], [10], [11], [23].…”

Section: Introductionmentioning

confidence: 99%

pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma

et al. 2017

View full text Add to dashboard Cite

Highly malignant brain tumors harbor the aberrant propensity for aerobic glycolysis, the excessive conversion of glucose to lactic acid even in the presence of ample tissue oxygen. Lactic acid is rapidly effluxed to the tumor microenvironment via a group of plasma-membrane transporters denoted monocarboxylate transporters (MCTs) to prevent “self-poisoning.” One isoform, MCT2, has the highest affinity for lactate and thus should have the ability to respond to microenvironment conditions such as hypoxia, lactate, and pH to help maintain high glycolytic flux in the tumor. Yet, MCT2 is considered to not respond to hypoxia, which is counterintuitive. Its response to tumor lactate has not been reported. In this report, we experimentally identify the transcription initiation site/s for MCT2 in astrocytes (normal) and glioma (tumor). We then use a BACmid library to isolate a 4.2-kbp MCT2 promoter-exon I region and examine promoter response to glycolysis-mediated stimuli in glioma cells. Reporter analysis of nested-promoter constructs indicated response of MCT2 to hypoxia, pH, lactate, and glucose, the major physiological “players” that facilitate a tumor's growth and proliferation. Immunoblot analysis of native MCT2 expression under altered pH and hypoxia reflected the reporter data. The pH-mediated gene-regulation studies we describe are the first to record H+-based reporter studies for any mammalian system and demonstrate the exquisite response of the MCT2 gene to minute changes in tumor pH. Identical promoter usage also provides the first evidence of astrocytes harnessing the same gene regulatory regions to facilitate astrocyte-neuron lactate shuttling, a metabolic feature of normal brain.

show abstract

Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: An immunohistochemical study

Cited by 26 publications

References 36 publications

A neuronal MCT2 knockdown in the rat somatosensory cortex reduces both the NMR lactate signal and the BOLD response during whisker stimulation

A neuronal MCT2 knockdown in the rat somatosensory cortex reduces both the NMR lactate signal and the BOLD response during whisker stimulation

Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma

Contact Info

Product

Resources

About