Uracil nucleotides: From metabolic intermediates to neuroprotection and neuroinflammation

Uracil nucleotides (i.e., UTP and UDP) have been known for years as fundamental intermediates in the de novo synthesis of the other pyrimidine nucleotides, which altogether represent key building blocks for nucleic acid synthesis. In addition, their sugar conjugates (i.e., UDP-glucose and UDP-galactose) enter in several biochemical routes, for example leading to glycogen biosynthesis, and protein and lipid glycosylation, which in turn contribute to the synthesis of essential components of the cellular plasma membrane. More recently, the existence of a “pyrimidinergic transmission” has arisen from the discovery that several purinergic G protein-coupled P2Y receptors can be activated also or exclusively by uracil nucleotides and sugar conjugates. The number of these receptors is continuously growing over years with the discovery that previously “orphan” G protein-coupled receptors are actually responding to this class of molecules. Therefore, new unforeseen effects mediated by uracil derivatives have emerged, in particular in the nervous system, and previously unexplored avenues for the pharmacological manipulation of this system are currently under investigation. In this commentary we shall try to put together our current knowledge on the biochemical and receptor-mediated effects of uracil nucleotide derivatives with a specific focus on the nervous system in order to depict a clearer view of the importance of the pyrimidinergic system in both physiological and pathological conditions.