Nucleoside recycling in the brain and the nucleosidome: a complex metabolic and molecular cross-talk between the extracellular nucleotide cascade system and the intracellular nucleoside salvage

The transports of nucleosides from blood into neurons and astrocytes are essential prerequisites to enter their metabolic utilization in brain. Adult brain does not possess the de novo nucleotide synthesis, and maintains its nucleotide pools by salvaging preformed nucleosides imported from liver. Once nucleosides enter the brain through the blood brain barrier and the nucleoside transporters, they become obligatory precursors for the synthesis of RNA and DNA and a plethora of other important functions. However, an aliquot of nucleotides are transferred into vesicular nucleotide transporters, and then in the extracellular space by exocytosis of the vesicles, where ATP and UTP interact with a vast heterogeneity of purine and pyrimidine receptors. Their signal actions are terminated by the ectonucleotidase cascade system, which degrades ATP and UTP into adenosine and uridine, respectively. The low specificity of the vesicular nucleotide transporters may explain the presence in the extracellular space of GTP and CTP, which are equally degraded to their respective nucleosides by the ectonucleotidases. The main four nucleosides are re-imported either into the same cell, or in adjacent cells, e.g. between two astrocytes, or between a neuron and an astrocyte, to regenerate nucleoside triphosphates. The molecular network of this metabolic cross-talk, involving the ectonucleotidases, the nucleoside transporters, the nucleotide salvage system, the nucleotide transport into the vesicular nucleotide transporters, and the exocytotic release of nucleotides, called by us the ‘‘nucleosidome’’, serves the nucleoside recycling in the brain, with a considerable spatial–temporal advantage