Origin, utilization, and recycling of nucleosides in the central nervous system

The brain relies on the salvage of preformed purine and pyrimidine rings, mainly in the form of nucleosides, to maintain its nucleotide pool in the proper qualitative and quantitative balance. The transport of nucleosides from blood into neurons and glia is considered to be an essential prerequisite to enter their metabolic utilization in the brain. Recent lines of evidence have also suggested that local extracellular nucleoside triphosphate (NTP) degradation may contribute to brain nucleosides. Plasma membrane-located ectonucleotidases, with their active sites oriented toward the extracellular space, catalyze the successive hydrolysis of NTPs to their respective nucleosides. Apart from the well-established modulation of ATP, ADP, adenosine (the purinergic agonists), UTP, and UDP (the pyrimidinergic agonists) availability at their respective receptors, ectonucleotidases may also serve the local reutilization of nucleosides in the brain. After their production in the extracellular space by the ectonucleotidase system, nucleosides are transported into neurons and glia and converted back to NTPs via a set of purine and pyrimidine salvage enzymes. Finally, nucleotides are transported into brain cell vescicles or granules and released back into the extracellular space. The key teaching concepts to be included in a two-to three-lecture block on the molecular mechanisms of the local nucleoside recycling process, based on a cross talk between the brain extracellular space and cytosol, are discussed in this article.