FIGURE 7.

Extracellular L-lactate controls cytosolic lactate synthesis via yet unidentified receptors coupled to adenylate cyclase activity and cytosolic cAMP increase in astrocytes. In the brain, L-lactate is formed in the cytoplasm of astrocytes (IN) and is released through monocarboxylate transporters (MCTs) 1,4 and/or lactate-permeable channels. Extracellularly (OUT), L-lactate can be transported to neighboring cells as a fuel. However, it can also act as a signaling molecule by binding to the L-lactate receptors of neighboring cells, stimulating adenylate cyclase activity (AC) and an increase in cAMP synthesis. Elevated cytosolic cAMP levels facilitate glycogen degradation by activating glycogen phosphorylase (GP) and glycolysis with L-lactate as the end product. In the absence of the L-lactate positive feedback mechanism (“metabolic excitability”), the L-lactate tissue concentration gradient could be dissipated, reducing the availability of L-lactate as a metabolic fuel, when local energy demands, especially in the brain, are high. This model shares similarities with the ‘autocrine lactate loop’ acting (oppositely) on [cAMP]_i through GPR81 receptor in adipocytes (Ahmed et al., 2010). GS, glycogen synthase; TCA, tricarboxylic acid cycle. Glucose denotes phosphorylated and free glucose.