Lactate Receptor Sites Link Neurotransmission, Neurovascular Coupling, and Brain Energy Metabolism

Abstract

The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. Cerebral GPR81 is concentrated on the synaptic membranes of excitatory synapses, with a postsynaptic predominance. GPR81 is also enriched at the blood-brain-barrier: the GPR81 densities at endothelial cell membranes are about twice the GPR81 density at membranes of perivascular astrocytic processes, but about one-seventh of that on synaptic membranes. There is only a slight signal in perisynaptic processes of astrocytes. In synaptic spines, as well as in adipocytes, GPR81 immunoreactivity is located on subplasmalemmal vesicular organelles, suggesting trafficking of the protein to and from the plasma membrane. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability.

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

“…Electron microscopic immunogold quantification showed the highest immunoreactivity at the postsynaptic membrane of excitatory type synapses on dendritic spines of pyramidal cells, but also a signal in vascular endothelial cells, i.e., at the BBB, and in perivascular and perisynaptic processes of astrocytes. 4 The action of lactate described in locus coeruleus 60 increases rather than suppresses cAMP levels and in contrast to HCAR1 is selective for L-lactate versus D-lactate. The authors therefore dismissed the option that the effects were mediated by HCAR1 and proposed that a yet unidentified receptor is involved.…”

“…It may signal in several ways, thus lactate modifies prostaglandin action contributing to vasomotor regulation, 57 and influences the NADH/NAD + ratio contributing to redox regulation. 5 Lactate signaling through a specific receptor protein, HCAR1, was shown in the brain only in 2013, 4 and the distribution of the protein ( Figures 1C, 1D, 1E, 1H, and 1I) was delineated the year before. 58 In a review, published in July 2013, 12 the possibility that HCAR1 mediates lactate action in brain was mentioned as an outstanding question-'Functional demonstration of HCAR1 in brain may reveal a whole new dimension to metabolic signaling in this organ'.…”

“…3 The latter concept was underpinned by the demonstration that lactate can bind to the lactate receptor GPR81 (hydroxycarboxylic acid receptor, HCAR1), on brain cells and cerebral blood vessels, resulting in inhibition of adenylyl cyclase. 4 The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain will be the focus of this review ( Figure 1). …”

A laktátdehidrogenáz (LDH) prognosztikai jelentősége az onkológiában

“…Az L-laktát természetes agonistája a GPR81-nek más monokarboxilátokkal együtt, mint az alfa-hidroxi-vajsav, glikolát, alfahidroxi-izo-vajsav és a gamma-hidroxi-vajsav [76,77]. A GPR81-et leírták zsírsejtekben [78], az agyszövetben [79], a májban és a vázizomban [80], ugyanakkor CRC, hepatocellularis carcinoma (HCC), emlő-, tüdő-, nyál-mirigy-, méhnyak-és hasnyálmirigyrák-sejtvonalakon, továbbá reszekált hasnyálmirigyrák-szövetekben is. Kimutatták, hogy a kis hajtű ribonukleinsav (shRNS) köz-vetítette GPR81-csendesítés alacsony glükóz-és tejsavtartalmú környezetben a daganatsejtek pusztulásához vezetett, azonban a glükózt tartalmazó táptalaj esetén a GPR81-csendesítésnek nem volt hatása.…”

“…Még nem tisztázott, hogy a tejsav és a GPR81 kapcsolata milyen folyamatokat indít be a daganatsejtekben. A tejsav az idegsejtekben például az activity-regulated cytoskeleton-associated protein (Arc), Finkel-Biskis-Jinkins-osteosarcoma (c-Fos) és a Zinc-finger protein 268 (Zif268) gének transzkripcióját váltja ki, amely folyamat az N-metil-D-aszpartát (NMDA) receptor és annak downstream jelátviteli kaszkádja, az Erk1/2 aktiválásához kötött [79]. A tejsav fokozza az intracelluláris NADH-képződést, így befolyásolva az idegsejtek redox státuszát [82].…”