Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport

Svichar, Nataliya; Chesler, Mitchell

doi:10.1002/glia.10187

Cited by 44 publications

(32 citation statements)

References 30 publications

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“…Gradual recovery of pH i in the presence of 20 mmol/L lactate has been also observed previously in cultured astrocytes and cultured or isolated neurons. 28,29 We conclude that addition of neither pyruvate nor lactate evokes a significant intracellular acidification that could affect the interpretation of our results.…”

Section: Contribution Of Neurons and Astrocytes To The Energy Productionmentioning

confidence: 80%

Glycolysis and Oxidative Phosphorylation in Neurons and Astrocytes during Network Activity in Hippocampal Slices

Ivanov

Malkov

Waseem

et al. 2013

J Cereb Blood Flow Metab

101

103

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Network activation triggers a significant energy metabolism increase in both neurons and astrocytes. Questions of the primary neuronal energy substrate (e.g., glucose vs. lactate) as well as the relative contributions of glycolysis and oxidative phosphorylation and their cellular origin (neurons vs. astrocytes) are still a matter of debates. Using simultaneous measurements of electrophysiological and metabolic parameters during synaptic stimulation in hippocampal slices from mature mice, we show that neurons and astrocytes use both glycolysis and oxidative phosphorylation to meet their energy demands. Supplementation or replacement of glucose in artificial cerebrospinal fluid (ACSF) with pyruvate or lactate strongly modifies parameters related to network activity-triggered energy metabolism. These effects are not induced by changes in ATP content, pH i , [Ca 2 þ ] i or accumulation of reactive oxygen species. Our results suggest that during network activation, a significant fraction of NAD(P)H response (its overshoot phase) corresponds to glycolysis and the changes in cytosolic NAD(P)H and mitochondrial FAD are coupled. Our data do not support the hypothesis of a preferential utilization of astrocyte-released lactate by neurons during network activation in slices-instead, we show that during such activity glucose is an effective energy substrate for both neurons and astrocytes. Keywords: astrocytes; energy metabolism; glycolysis; lactate; network activity; neurons INTRODUCTION High cellular energy demands during network activation are met by upregulation of cytosolic glycolysis and mitochondrial oxidative phosphorylation. Mitochondrial metabolism provides most of the ATP but glycolysis is also enhanced and may contribute to the energy production. Journal of Cerebral Blood1-4 For elucidation of the cellular basis of neuroenergetics, measurements of metabolic signals including the oxygen utilization and NAD(P)H/FAD autofluorescence provide valuable information for connecting energy metabolism with neuronal activity. NADH (reduced form) is fluorescent when excited with UV light whereas NAD þ is not, leading to a decrease in observed fluorescence as a result of NADH oxidation. In contrast, FAD (oxidized form) is fluorescent, so the oxidation of FADH 2 to FAD causes an increase in fluorescence. The fluorescence of NADH cannot be separated from that of NADPH and their emission is measured in concert (NAD(P)H). NAD(P)H fluorescence represents a 'mixed' signal since this cofactor can be produced by both glycolysis and mitochondria, whereas FAD fluorescence is entirely mitochondrial. 5,6 Measurements of these parameters in combination with electrophysiological recordings have been used in many studies to monitor the energy status during neuronal activity in brain tissues.Typically, NAD(P)H transients induced by synaptic stimulation have a characteristic biphasic waveform: the initial short dip is followed by a long-lasting overshoot. While there exists a common

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Section: Contribution Of Neurons and Astrocytes To The Energy Productionmentioning

confidence: 80%

Glycolysis and Oxidative Phosphorylation in Neurons and Astrocytes during Network Activity in Hippocampal Slices

Ivanov

Malkov

Waseem

et al. 2013

J Cereb Blood Flow Metab

101

103

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“…However, it has been suggested recently that a widespread neuronal expression of CAII takes place in the brain, including the hippocampus (Wang et al, 2002). Other catalytic carbonic anhydrase isoforms in the parenchyma of the mammalian brain include the extracellular isoforms IV and XIV (Parkkila et al, 2001;Svichar and Chesler 2003) and the mitochondrial carbonic anhydrase CAV (Ghandour et al, 2000).…”

Section: Identification Of the Intrapyramidal Carbonic Anhydrase Isoformmentioning

confidence: 99%

Carbonic Anhydrase Isoform VII Acts as a Molecular Switch in the Development of Synchronous Gamma-Frequency Firing of Hippocampal CA1 Pyramidal Cells

Ruusuvuori¹,

Li²,

Huttu³

et al. 2004

J. Neurosci.

138

124

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Identification of the molecular mechanisms that enable synchronous firing of CA1 pyramidal neurons is central to the understanding of the functional properties of this major hippocampal output pathway. Using microfluorescence measurements of intraneuronal pH, in situ hybridization, as well as intracellular, extracellular, and K ϩ -sensitive microelectrode recordings, we show now that the capability for synchronous gamma-frequency (20 -80 Hz) firing in response to high-frequency stimulation (HFS) emerges abruptly in the rat hippocampus at approximately postnatal day 12. This was attributable to a steep developmental upregulation of intrapyramidal carbonic anhydrase isoform VII, which acts as a key molecule in the generation of HFS-induced tonic GABAergic excitation. These results point to a crucial role for the developmental expression of intrapyramidal carbonic anhydrase VII activity in shaping integrative functions, long-term plasticity and susceptibility to epileptogenesis.

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“…In addition, it has been shown that extracellular carbonic anhydrase activity facilitates lactic acid transport in rat skeletal muscle fibers (21). In the brain CAII is highly expressed in astrocytes where it plays a supportive role in pH regulation (22) and supports the lactate shuttle from astrocytes to neurons (23).…”

mentioning

confidence: 99%

Nonenzymatic Proton Handling by Carbonic Anhydrase II during H+-Lactate Cotransport via Monocarboxylate Transporter 1

Becker

Deitmer

2008

Journal of Biological Chemistry

105

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Carbonic anhydrase (CA) is a ubiquitous enzyme catalyzing the equilibration of carbon dioxide, protons, and bicarbonate. For several acid/base-coupled membrane carriers it has been shown that the catalytic activity of CA supports transport activity, an interaction coined "transport metabolon." We have reported that CA isoform II (CAII) enhances lactate transport activity of the monocarboxylate transporter isoform I (MCT1) expressed in Xenopus oocytes, which does not require CAII catalytic activity (Becker, H. M., Fecher-Trost, C., Hirnet, D., Sült-emeyer, D., and Deitmer, J. W. (2005) J. Biol. Chem. 280, 39882-39889). Coexpression of MCT1 with either wild type CAII or the catalytically inactive mutant CAII-V143Y similarly enhanced MCT1 activity, although injection of CAI or coexpression of an N-terminal mutant of CAII had no effect on MCT1 transport activity, demonstrating a specific, nonenzymatic action of CAII on lactate transport via MCT1. If the H ؉ gradient was set to dominate the rate of lactate transport by applying low concentrations of lactate at a high H ؉ concentration, the effect of CAII was largest. We tested the hypothesis of whether CAII helps to shuttle H ؉ along the inner face of the cell membrane by measuring the pH change with fluorescent dye in different areas of interest during focal lactate application. Intracellular pH shifts decayed from the focus of lactate application to more distant sites much less when CAII had been injected. We present a hypothetical model in which the effective movement of H ؉ into the bulk cytosol is increased by CAII, thus slowing the dissipation of the H ؉ gradient across the cell membrane, which drives MCT1 activity.Transport of acid/base equivalents across cell membranes plays a crucial role both for pH regulation and cellular import and export of metabolites. Many Na ϩ -dependent and Na ϩ -independent transport modes of metabolites (e.g. neurotransmitter substances) also transport H ϩ , OH Ϫ , or HCO 3 Ϫ as co-or counter-substrate. The energetic compounds lactate and pyruvate are primarily transported by monocarboxylate transporters (MCT) 2 in an electroneutral 1 proton-1 organic anion transport mode. Members of the MCT family, which belong to the human gene family SLC16 which comprise 14 isoforms, are expressed in most tissues, in particular those with a large energy consumption like muscle and brain (1, 2). In the brain MCT1 is located mainly in glial cells, where it facilitates the export of lactate, which is then taken up by neurons via the high affinity MCT2; thereby the two isoforms are believed to shuttle lactate from glial cells to neurons which seems to be pivotal for brain energy metabolism (3-6). In muscle, MCT1 is highly expressed in oxidative type I fibers, where it mediates import of lactate that is released by glycolytic muscle cells via MCT3 and MCT4 (7-9). MCT1, when expressed in Xenopus oocytes, operates with a K m value of 3.5 mM for lactate influx and of 6.4 mM for efflux of lactate. Both the rate and the amplitude of the lactate-induced ac...

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Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport

Cited by 44 publications

References 30 publications

Glycolysis and Oxidative Phosphorylation in Neurons and Astrocytes during Network Activity in Hippocampal Slices

Glycolysis and Oxidative Phosphorylation in Neurons and Astrocytes during Network Activity in Hippocampal Slices

Carbonic Anhydrase Isoform VII Acts as a Molecular Switch in the Development of Synchronous Gamma-Frequency Firing of Hippocampal CA1 Pyramidal Cells

Nonenzymatic Proton Handling by Carbonic Anhydrase II during H+-Lactate Cotransport via Monocarboxylate Transporter 1

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