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