Astrocytes have a number of important functions in the central nervous system. They participate in the metabolism; they metabolize glucose to lactate, which can then be transported to the neurons. Metabolism of astrocytes is carefully regulated by the G-protein coupled receptors, including the GPR40, a receptor for free fatty acids. Since the impact of GPR40 activation on intracellular signal pathways and metabolism of astrocytes in the central nervous system has not been explored, the purpose here was to determine how the endogenous, nonselective GPR40 receptor agonist oleic acid and the synthetic selective agonist TAK875 affect the intracellular concentration of secondary messengers Ca2+, cAMP and metabolite lactate in cortical astrocytes in culture. By using the fluorescent Ca2+ indicator Fluo4-AM and real time fluorescent microscopy, the results revealed that oleic acid and TAK875 have no effect on the intracellular concentration of Ca2+ in rat astrocytes in culture. By using genetically encoded FRET (Förster resonance energy transfer)-nanosensors Epac1-camps for cAMP and Laconic for lactate and FRET-microscopy, the results show that oleic acid and TAK875 increase the intracellular cAMP and lactate concentration in astrocytes. It can be concluded that GPR40 receptor agonists, oleic acid and TAK875 are activating a signal pathway via the Gs-protein and the adenylate cyclase, causing a rise in the concentration of cAMP. This can then activate protein kinase A, which can then stimulate glycogen breakdown and aerobic glycolysis in astrocytes. It is proposed that the astrocytic GPR40 receptors play a role in the regulation of central nervous system metabolism, because in astrocytes they activate the production of lactate, which can then be transferred to neurons and used as a metabolite and a signalling molecule.
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