Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

Nina Vardjan; Helena H. Chowdhury; Anemari Horvat; Jelena Velebit; Maja Malnar; Marko Muhič; Marko Kreft; Špela G. Krivec; Saša T. Bobnar; Katarina Miš; Sergej Pirkmajer; Stefan Offermanns; Gjermund Henriksen; Jon Storm-mathisen; Linda H. Bergersen; Robert Zorec

doi:10.3389/fnmol.2018.00148

Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

Nina Vardjan, Helena H. Chowdhury, Anemari Horvat, Jelena Velebit, Maja Malnar, Marko Muhič, Marko Kreft, Špela G. Krivec, Saša T. Bobnar, Katarina Miš, Sergej Pirkmajer, Stefan Offermanns, Gjermund Henriksen, Jon Storm-mathisen, Linda H. Bergersen, Robert Zorec

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Abstract

Besides being a neuronal fuel, L-lactate is also a signal in the brain. Whether extracellular L-lactate affects brain metabolism, in particular astrocytes, abundant neuroglial cells, which produce L-lactate in aerobic glycolysis, is unclear. Recent studies suggested that astrocytes express low levels of the L-lactate GPR81 receptor (EC50 ≈ 5 mM) that is in fat cells part of an autocrine loop, in which the Gi-protein mediates reduction of cytosolic cyclic adenosine monophosphate (cAMP). To study whether a similar signaling loop is present in astrocytes, affecting aerobic glycolysis, we measured the cytosolic levels of cAMP, D-glucose and L-lactate in single astrocytes using fluorescence resonance energy transfer (FRET)-based nanosensors. In contrast to the situation in fat cells, stimulation by extracellular L-lactate and the selective GPR81 agonists, 3-chloro-5-hydroxybenzoic acid (3Cl-5OH-BA) or 4-methyl-N-(5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (Compound 2), like adrenergic stimulation, elevated intracellular cAMP and L-lactate in astrocytes, which was reduced by the inhibition of adenylate cyclase. Surprisingly, 3Cl-5OH-BA and Compound 2 increased cytosolic cAMP also in GPR81-knock out astrocytes, indicating that the effect is GPR81-independent and mediated by a novel, yet unidentified, excitatory L-lactate receptor-like mechanism in astrocytes that enhances aerobic glycolysis and L-lactate production via a positive feedback mechanism.

Original language	English
Article number	148
Journal	Frontiers in Molecular Neuroscience
Volume	11
Number of pages	15
ISSN	1662-5099
DOIs	https://doi.org/10.3389/fnmol.2018.00148
Publication status	Published - 8 May 2018

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Vardjan, N., Chowdhury, H. H., Horvat, A., Velebit, J., Malnar, M., Muhič, M., Kreft, M., Krivec, Š. G., Bobnar, S. T., Miš, K., Pirkmajer, S., Offermanns, S., Henriksen, G., Storm-mathisen, J., Bergersen, L. H., & Zorec, R. (2018). Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP. Frontiers in Molecular Neuroscience, 11, Article 148. https://doi.org/10.3389/fnmol.2018.00148

Vardjan, N, Chowdhury, HH, Horvat, A, Velebit, J, Malnar, M, Muhič, M, Kreft, M, Krivec, ŠG, Bobnar, ST, Miš, K, Pirkmajer, S, Offermanns, S, Henriksen, G, Storm-mathisen, J, Bergersen, LH & Zorec, R 2018, 'Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP', Frontiers in Molecular Neuroscience, vol. 11, 148. https://doi.org/10.3389/fnmol.2018.00148

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title = "Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP",

abstract = "Besides being a neuronal fuel, L-lactate is also a signal in the brain. Whether extracellular L-lactate affects brain metabolism, in particular astrocytes, abundant neuroglial cells, which produce L-lactate in aerobic glycolysis, is unclear. Recent studies suggested that astrocytes express low levels of the L-lactate GPR81 receptor (EC50 ≈ 5 mM) that is in fat cells part of an autocrine loop, in which the Gi-protein mediates reduction of cytosolic cyclic adenosine monophosphate (cAMP). To study whether a similar signaling loop is present in astrocytes, affecting aerobic glycolysis, we measured the cytosolic levels of cAMP, D-glucose and L-lactate in single astrocytes using fluorescence resonance energy transfer (FRET)-based nanosensors. In contrast to the situation in fat cells, stimulation by extracellular L-lactate and the selective GPR81 agonists, 3-chloro-5-hydroxybenzoic acid (3Cl-5OH-BA) or 4-methyl-N-(5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (Compound 2), like adrenergic stimulation, elevated intracellular cAMP and L-lactate in astrocytes, which was reduced by the inhibition of adenylate cyclase. Surprisingly, 3Cl-5OH-BA and Compound 2 increased cytosolic cAMP also in GPR81-knock out astrocytes, indicating that the effect is GPR81-independent and mediated by a novel, yet unidentified, excitatory L-lactate receptor-like mechanism in astrocytes that enhances aerobic glycolysis and L-lactate production via a positive feedback mechanism.",

author = "Nina Vardjan and Chowdhury, {Helena H.} and Anemari Horvat and Jelena Velebit and Maja Malnar and Marko Muhi{\v c} and Marko Kreft and Krivec, {{\v S}pela G.} and Bobnar, {Sa{\v s}a T.} and Katarina Mi{\v s} and Sergej Pirkmajer and Stefan Offermanns and Gjermund Henriksen and Jon Storm-mathisen and Bergersen, {Linda H.} and Robert Zorec",

year = "2018",

month = may,

day = "8",

doi = "10.3389/fnmol.2018.00148",

language = "English",

volume = "11",

journal = "Frontiers in Molecular Neuroscience",

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T1 - Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

AU - Vardjan, Nina

AU - Chowdhury, Helena H.

AU - Horvat, Anemari

AU - Velebit, Jelena

AU - Malnar, Maja

AU - Muhič, Marko

AU - Kreft, Marko

AU - Krivec, Špela G.

AU - Bobnar, Saša T.

AU - Miš, Katarina

AU - Pirkmajer, Sergej

AU - Offermanns, Stefan

AU - Henriksen, Gjermund

AU - Storm-mathisen, Jon

AU - Bergersen, Linda H.

AU - Zorec, Robert

PY - 2018/5/8

Y1 - 2018/5/8

N2 - Besides being a neuronal fuel, L-lactate is also a signal in the brain. Whether extracellular L-lactate affects brain metabolism, in particular astrocytes, abundant neuroglial cells, which produce L-lactate in aerobic glycolysis, is unclear. Recent studies suggested that astrocytes express low levels of the L-lactate GPR81 receptor (EC50 ≈ 5 mM) that is in fat cells part of an autocrine loop, in which the Gi-protein mediates reduction of cytosolic cyclic adenosine monophosphate (cAMP). To study whether a similar signaling loop is present in astrocytes, affecting aerobic glycolysis, we measured the cytosolic levels of cAMP, D-glucose and L-lactate in single astrocytes using fluorescence resonance energy transfer (FRET)-based nanosensors. In contrast to the situation in fat cells, stimulation by extracellular L-lactate and the selective GPR81 agonists, 3-chloro-5-hydroxybenzoic acid (3Cl-5OH-BA) or 4-methyl-N-(5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (Compound 2), like adrenergic stimulation, elevated intracellular cAMP and L-lactate in astrocytes, which was reduced by the inhibition of adenylate cyclase. Surprisingly, 3Cl-5OH-BA and Compound 2 increased cytosolic cAMP also in GPR81-knock out astrocytes, indicating that the effect is GPR81-independent and mediated by a novel, yet unidentified, excitatory L-lactate receptor-like mechanism in astrocytes that enhances aerobic glycolysis and L-lactate production via a positive feedback mechanism.

AB - Besides being a neuronal fuel, L-lactate is also a signal in the brain. Whether extracellular L-lactate affects brain metabolism, in particular astrocytes, abundant neuroglial cells, which produce L-lactate in aerobic glycolysis, is unclear. Recent studies suggested that astrocytes express low levels of the L-lactate GPR81 receptor (EC50 ≈ 5 mM) that is in fat cells part of an autocrine loop, in which the Gi-protein mediates reduction of cytosolic cyclic adenosine monophosphate (cAMP). To study whether a similar signaling loop is present in astrocytes, affecting aerobic glycolysis, we measured the cytosolic levels of cAMP, D-glucose and L-lactate in single astrocytes using fluorescence resonance energy transfer (FRET)-based nanosensors. In contrast to the situation in fat cells, stimulation by extracellular L-lactate and the selective GPR81 agonists, 3-chloro-5-hydroxybenzoic acid (3Cl-5OH-BA) or 4-methyl-N-(5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (Compound 2), like adrenergic stimulation, elevated intracellular cAMP and L-lactate in astrocytes, which was reduced by the inhibition of adenylate cyclase. Surprisingly, 3Cl-5OH-BA and Compound 2 increased cytosolic cAMP also in GPR81-knock out astrocytes, indicating that the effect is GPR81-independent and mediated by a novel, yet unidentified, excitatory L-lactate receptor-like mechanism in astrocytes that enhances aerobic glycolysis and L-lactate production via a positive feedback mechanism.

U2 - 10.3389/fnmol.2018.00148

DO - 10.3389/fnmol.2018.00148

M3 - Journal article

C2 - 29867342

SN - 1662-5099

VL - 11

JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

M1 - 148

ER -

Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

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