The lactate receptor, G‐protein‐coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain

Abstract

We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA 1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippocampus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce cAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the bloodbrain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucoseand glycogen-saving response. HCAR1 may contribute to optimizing the cAMP concentration. For instance, in the prefrontal cortex, excessively high cAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells. V C 2015 Wiley Periodicals, Inc.Key words: lactate; volume transmitter; cAMP; hippocampus L-lactate, pyruvate, and the ketone bodies bhydroxybutyrate and acetoacetate are monocarboxylates that are carried across different cell membranes by monocarboxylate transporters (MCTs; Poole and Halestrap, 1994;Bergersen et al., 1999Bergersen et al., , 2001Pierre et al., 2000; for review see Bergersen, 2007Bergersen, , 2015Halestrap, 2013). Llactate is the most abundant MCT substrate in the brain, and its cerebral concentration varies based on, for instance, metabolic rate, oxygen availability, neuronal firing, and serum lactate levels. The MCTs mediate facilitated cotransport of monocarboxylate anion and proton, meaning that they serve to equilibrate substrate concentrations across cell membranes, with the combined concentration gradients of monocarboxylate and proton as the driving force. Hence, L-lactate and other MCT substrates migrate from sites of production toward sites of consumption, such as between different cells within an organ or among different organs via the blood stream. The equilibrating diffusion of lactate via MCTs between cells and the extracellular space provide a basis for lactate acting as a "volume transmitter" because it allows lactate

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

“…Therefore, HCAR1 can respond to lactate within the full concentration range reported in vivo (0.5–30 mM in blood and brain extracellular fluid, see review ref. 32). …”

Aging‐associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte‐to‐neuron lactate shuttle

“…The “energetic” explanation is that the lactate being a substrate for neuronal oxidative phosphorylation may directly, via increase in ATP synthesis (for review see Obel et al, ), and/or indirectly, via postsynaptic changes in NADH, potentiate NMDA signaling (Yang et al, ). In contrast, it cannot be excluded that lactate plays a role of an autocrine signaling molecule (Morland et al, ). Our study support the “energetic” hypothesis, but only in young mice.…”

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…Another possible role of lactate is as a ligand of hydroxycarboxylic acid receptor 1 (HCAR1) expressed in neurons . HCAR1, a G‐protein coupled receptor, suppresses neuronal excitability by increasing the intracellular cAMP concentration.…”

“…Another possible role of lactate is as a ligand of hydroxycarboxylic acid receptor 1 (HCAR1) expressed in neurons. 106,107 HCAR1, a G-protein coupled receptor, suppresses neuronal excitability by increasing the intracellular cAMP concentration. Irrespective of the origin of lactate, direct evidence supports that extracellular lactate regulates synaptic activity (i.e., mainly inhibitory effects) and that the disinhibition of neuronal excitation can cause intractable epilepsy.…”