Figure 2.

L-lactate-mediated signaling in the central nervous system. (A) GPR81-mediated signaling. GPR81 (HCA1) was reported to be expressed in the brain, mostly in neurons. It couples to G_i proteins, leading to adenylate cyclase (AC) inhibition and reduced cAMP production. L-lactate activates GPR81 at concentrations above 2.5 mmol/l (studies often use 5 to 10 mmol/L). (B) G_s protein-coupled receptor mediated signaling. Astrocyte-derived L-lactate excites noradrenergic cells in the locus coeruleus in a concentration-dependent manner. This effect is mediated by a putative G_s-coupled receptor, and accompanied with accumulation of cAMP and activation of protein kinase A (PKA). Estimated EC₅₀ for this effect of L-lactate was ~600 μmol/L. (C) K_ATP channel-mediated signaling in orexin neurons. Astrocyte-derived L-lactate enters neurons through monocarboxylate transporter 2 (MCT2), is metabolized to pyruvate and used for generation of ATP in tricarboxylic acid (TCA) cycle. This causes a shift in intracellular ATP/ADP ratio, this closes K_ATP channels leading to membrane depolarization and neuronal excitation. (D) NMDA receptor-modulated signaling. L-lactate transported by MCT2 into hippocampal neurons is converted into pyruvate, causing an increase in intracellular NADH/NAD⁺ ratio that results in potentiation of NMDA receptor activity, Ca²⁺ influx and Erk1/2 phosphorylation. Via this route L-lactate could enhance expression of plasticity-related genes Arc, c-Fos, Zif268, and BDNF. These effects required high concentrations of L-lactate (10 to 20 mmol/L). Also note that there is evidence that extracellular acidification as may be expected when lactate builds up in the tissue, inhibits NMDA receptors (see text for details). Lac, L-lactate; Pyr, pyruvate.