Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain

Abstract

Monocarboxylate transporters (MCTs) are involved in the uptake and release of lactate, pyruvate, and ketone bodies. Studies of their distribution at both the mRNA and protein levels have highlighted the specific expression of MCT1, MCT2, and more recently MCT4 in the central nervous system. MCT1 was found strongly expressed by cortical astrocytes both in vitro and in vivo. It was also found at high levels on blood vessels, ependymocytes, and glia limitans. A subset of neurons in vitro exhibited a weak but significant MCT1 expression. In contrast, it was determined that MCT2 represents the predominant neuronal MCT on cultured neurons as well as on neurons throughout the brain parenchyma. At the subcellular level, part of MCT2 is located in postsynaptic densities. Specific populations of astrocytes in the white matter also exhibited MCT2 expression in the rat, but not in the mouse brain. MCT4 was found exclusively in astrocytes in several areas including the cortex, the hippocampus, and the cerebellum. MCT2 expression increased in cultured neurons with days in vitro commensurate with increased synapse formation. Moreover, a significant increase in MCT2 expression was observed in cultured neurons exposed to noradrenaline, an effect involving a regulation at the translational level. The description of MCTs on different cell types in the central nervous system together with clear evidence for regulation of their expression further emphasize the important role that monocarboxylates, and particularly lactate, might play in brain energy metabolism not only during development but also in the adult.

Basigin (CD147) Is the Target for Organomercurial Inhibition of Monocarboxylate Transporter Isoforms 1 and 4

“…Here we show that it is gp70 that fulfils this role. This is an important observation in view of the critical role that MCT2 is thought to play in lactate uptake as a fuel for neurones, especially in the synapses (39,40). Our data also provide a satisfying explanation as to why transport by MCT2 is insensitive to organomercurials while remaining sensitive to CHC and stilbene disulfonates that do not disrupt the MCT/ancillary protein interaction (Fig.…”

Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia

“…Lactic acid plays a key role in the nutrition of tissues like retina, brain, heart, and fast-twitch muscle fibers (6,20,21). In the retina, lactate is a major nutrient for rods and cones and reaches a concentration 10 times higher than in blood upon production by Müller cells (22).…”

Induction of Fos Immunoreactivity Labeling in Rat Forebrain Metabolic Loci by Caudal Fourth Ventricular Infusion of the Monocarboxylate Transporter Inhibitor, Alpha-Cyano-4-Hydroxycinnamic Acid

“…Astrocytic release of lactate into the extracellular compartment and neuronal uptake of this molecule occur via cell-type specific monocarboxyate transporter function [9]. Evidence for dose-proportionate induction of hyperglycemia by 4CIN suggests that counterregulatory hormone secretion occurs in response to periventricular caudal hindbrain detection of diminished uptake and/or catabolism of lactate [11].…”

“…MCT2 is the predominant variant expressed by central neurons (8b), but is also expressed by astrocytes in specific white matter structures [30]. MCT4 is expressed solely by astrocytes in several brain regions [9]. Since 4CIN is reported to inhibit both MCT1 and MCT2 function, albeit to a differential extent [18], it can be assumed that drug effects on these transporters in tissue accessible from the CV4 infusion site would result in inhibition of astrocytic release as well as neuronal uptake of lactate from the extracellular compartment of the caudal hindbrain.…”

“…Glucose enters the brain primarily by GLUT1 transporter-mediated uptake into astrocytes, where it is metabolized via the glycolytic pathway to yield the oxidizable fuel, lactate, for export into the extracellular space [6,7,8]. Unidirectional trafficking between glial and neuronal compartments involves cell-type-specific plasma membrane monocarboxylate transporter (MCT) function [9]. Emerging studies support the notion that lactate is a critical ‘sensed’ variable in monitoring of metabolic deficiency in the NTS/AP [10,11,12].…”