Fig. 2
Regulatory roles of adenosine in neurons and glial cells. a Neuronal activity is modulated by the cross talk between neurons and glial cells (i.e., microglia and astrocytes). b Adenosine is an important modulator in the brain. In neurons, upon activation, glutamate and ATP are released from the presynaptic terminal to activate receptors in the synapse, which modulates neuronal activity, calmodulin-mediated regulation of ENT affinity to transport adenosine, and adenosinergic pathways (as shown in Fig. 1). In microglia, released ATP can attract microglia by activating P2RY12. ATP can be quickly hydrolyzed into AMP and adenosine by ectonucleotidases (e.g., CD39 and CD73), which are enriched on the membrane of microglia and expressed on neurons and astrocytes. The resultant adenosine then activates neuronal ARs (e.g., A1R and A2AR) to suppress or facilitate the further release of neurotransmitters from the presynaptic terminal. In astrocytes, adenosine can also regulate the metabolism of astrocytes and the astrocytic transcriptome via the activation of AR (i.e., A2BR). ADK, adenosine kinase; AK, adenylate kinase; AMPK, AMP-activated protein kinase; ARs, adenosine receptors; CaM, calmodulin; ENTs, equilibrative nucleoside transporters; GluRs, glutamate receptors; and P2RY12, purinergic receptor P2Y, G-protein coupled, 12