Transport ofl-lactate by cultured rat brain astrocytes

Tildón, J. Tyson; McKenna, Mary C.; Stevenson, Joseph; Couto, R.

doi:10.1007/bf01474682

Cited by 87 publications

(93 citation statements)

References 33 publications

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“…Additionally, cultured neurons, astrocytes, and oligodendrocytes have the capacity to transport and utilize lactate, pyruvate, and ketone bodies (8,32,38). These studies have also indicated that lactate transport is saturable, proton dependent, and inhibited by cinnamates (1,7,22,34), all of which are characteristics of the MCT (reviewed in Ref. 27).…”

Section: Discussionmentioning

confidence: 98%

Monocarboxylate transporter expression in mouse brain

Koehler-Stec

Simpson

Vannucci

et al. 1998

American Journal of Physiology-Endocrinology and Metabolism

129

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. Monocarboxylate transporter expression in mouse brain. Am. J. Physiol. 275 (Endocrinol. Metab. 38): E516-E524, 1998.-Although glucose is the major metabolic fuel needed for normal brain function, monocarboxylic acids, i.e., lactate, pyruvate, and ketone bodies, can also be utilized by the brain as alternative energy substrates. In most mammalian cells, these substrates are transported either into or out of the cell by a family of monocarboxylate transporters (MCTs), first cloned and sequenced in the hamster. We have recently cloned two MCT isoforms (MCT1 and MCT2) from a mouse kidney cDNA library. Northern blot analysis revealed that MCT1 mRNA is ubiquitous and can be detected in most tissues at a relatively constant level. MCT2 expression is more limited, with high levels of expression confined to testes, kidney, stomach, and liver and lower levels in lung, brain, and epididymal fat. Both MCT1 mRNA and MCT2 mRNA are detected in mouse brain using antisense riboprobes and in situ hybridization. MCT1 mRNA is found throughout the cortex, with higher levels of hybridization in hippocampus and cerebellum. MCT2 mRNA was detected in the same areas, but the pattern of expression was more specific. In addition, MCT1 mRNA, but not MCT2, is localized to the choroid plexus, ependyma, microvessels, and white matter structures such as the corpus callosum. These results suggest a differential expression of the two MCTs at the cellular level. monocarboxylate transporter-1; monocarboxylate transporter-2; cDNA sequences; in situ hybridization

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Section: Discussionmentioning

confidence: 98%

Monocarboxylate transporter expression in mouse brain

Koehler-Stec

Simpson

Vannucci

et al. 1998

American Journal of Physiology-Endocrinology and Metabolism

129

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“…In previous studies, carrier-mediated uptake of lactate into astrocytes was blocked by millimolar concentrations of 4-CIN (Tildon et al, 1993;Broer et al, 1997). Application of 4-CIN (5 mM) reversibly inhibited the LIA in cortical astrocytes (Fig.…”

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confidence: 90%

“…Astrocytes have been found to express predominantly MCT1, while neurons appeared to express principally MCT2 (Broer et al, 1997). The ability of various transport inhibitors to nearly abolish lactate influx into astrocytes (Tildon et al, 1993;Broer et al, 1997) indicates that the passive influx of lactic acid across the lipid bilayer plays a small role. This is likely to be the case in the present study as well, given the large inhibition of the LIA by 4-CIN; however, a small nonfacilitated component of lactate entry cannot be ruled out.…”

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confidence: 99%

Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport

Svichar

Chesler

2003

Glia

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A number of studies have provided physiological evidence for extracellular carbonic anhydrase (CA) in brain. Association of extracellular CA with glia has been limited to functional studies of gliotic slices and retinal Muller cells. While astrocytes contain intracellular CA, there has been no direct evidence for surface CA on these cells. In fact, some morphological studies suggest that the extracellular CA in brain parenchyma resides on neurons, not glia. There has been no functional demonstration of extracellular CA activity on CNS neurons, however. Here we capitalized on the H ϩ dependence of inward lactate transport to reveal functional extracellular CA activity on cultured astrocytes and acutely isolated hippocampal pyramidal neurons. Exposure to 20 mM L-lactate produced a rapid acidification of astrocytes that was reversibly blocked by 10 M benzolamide. The lactate-induced acidification (LIA) was also blocked by a dextran-conjugated CA inhibitor. In CO 2 /HCO 3 Ϫ -free, HEPES-buffered media, the LIA was largely unaffected. Acutely dissociated hippocampal pyramidal neurons underwent a similar LIA that was reversibly blocked by benzolamide. Surface CA is likely to facilitate lactate transport by enabling rapid replenishment (i.e., buffering) of surface H ϩ required for inward lactate-H ϩ cotransport. These results demonstrate functional surface CA for the first time on individual mammalian astrocytes and neurons and suggest that this enzyme may play a role in the utilization of monocarboxylate substrates such as lactate and pyruvate by the brain. GLIA 41:415-419, 2003.

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“…In other studies, no high-affinity uptake was observed (Dringen et al, 1995). In the case of astrocytes, the wide range of K m (7 to > 15 mmol/L) and V max (174 to 250 nmol/min per mg) values that have been observed can probably be attributed to the relative extents to which MCT1 and MCT4 are expressed in the particular culture (Broer et al, 1997;Manning Fox et al, 2000;Tildon et al, 1993). …”

mentioning

confidence: 99%

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

Simpson

Carruthers

Vannucci

2007

J Cereb Blood Flow Metab

692

749

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Glucose is the obligate energetic fuel for the mammalian brain, and most studies of cerebral energy metabolism assume that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state. Glucose transporter (GLUT) proteins deliver glucose from the circulation to the brain: GLUT1 in the microvascular endothelial cells of the blood-brain barrier (BBB) and glia; GLUT3 in neurons. Lactate, the glycolytic product of glucose metabolism, is transported into and out of neural cells by the monocarboxylate transporters (MCT): MCT1 in the BBB and astrocytes and MCT2 in neurons. The proposal of the astrocyte-neuron lactate shuttle hypothesis suggested that astrocytes play the primary role in cerebral glucose utilization and generate lactate for neuronal energetics, especially during activation. Since the identification of the GLUTs and MCTs in brain, much has been learned about their transport properties, that is capacity and affinity for substrate, which must be considered in any model of cerebral glucose uptake and utilization. Using concentrations and kinetic parameters of GLUT1 and -3 in BBB endothelial cells, astrocytes, and neurons, along with the corresponding kinetic properties of the MCTs, we have successfully modeled brain glucose and lactate levels as well as lactate transients in response to neuronal stimulation. Simulations based on these parameters suggest that glucose readily diffuses through the basal lamina and interstitium to neurons, which are primarily responsible for glucose uptake, metabolism, and the generation of the lactate transients observed on neuronal activation. Keywords: glucose and lactate; glucose transporter proteins; mathematical modeling; monocarboxylate transporters; neurons and astrocytes; substrate delivery and metabolism IntroductionThe central dogma of cerebral energy metabolism is that glucose is the obligate energetic fuel of the mammalian brain and the only substrate able to completely sustain neural activity (Siesjo, 1978). Furthermore, it has traditionally been assumed that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state (Sokoloff et al, 1977). Rates of cerebral blood flow directly relate to measurements of cerebral oxygen consumption, generating the concept of the 'flow-metabolism couple' (Sokoloff, 1976;Sokoloff et al, 1977). The introduction of neuroimaging techniques to study cerebral metabolism revealed an 'uncoupling' between cerebral oxygen consumption, blood flow, and glucose utilization during brain activation (Fox and Raichle, 1986; Fox et al, 1988), with the suggestion of regional stimulation of oxidative glycolysis during neuronal activation. The temporal relationship between the release of lactate and the onset of neuronal activation, the source of the lactate, that is neuronal or glial, and its subsequent diffusion and disposal are all matters of considerable debate. Initial studies by Prichard et al (1991) assu...

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Transport ofl-lactate by cultured rat brain astrocytes

Cited by 87 publications

References 33 publications

Monocarboxylate transporter expression in mouse brain

Monocarboxylate transporter expression in mouse brain

Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport

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

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