Metabolic interplay between intra- and extra-cellular uridine metabolism via an ATP driven uridine-UTP cycle in brain

Undine, a pyrimidine nucleoside essential for the synthesis of RNA and biomembranes, has several trophic functions in the central nervous system, that involve a physiological regulation of pyrimidine nucleotides and phospholipids content, and a maintenance of brain metabolism under ischemia, or pathological situations The understanding of uridine production in the brain is therefore of fundamental Importance Brain has a limited capacity to synthesize ex novo the pyrimidine ring, and a reasonable source of brain undine is UTP The kinetics of UTP breakdown, as catalysed by post-mitochondrial brain extracts and membrane preparations reported herein suggests that in normoxic conditions uridine is locally generated in brain exclusively in the extracellular space, and that any uptaken undine is salvaged to UTP It is now well established that cytosolic UTP can be released to Interact with a subset of P2Y receptors, inducing a variety of molecular and cellular effects, leading to neuroprotection, while uridine is uptaken via an equilibrative or a Na+-dependent transport system, to exert its trophic effects in the cytosol An ATP driven uridine-UTP cycle can be envisaged, based on the strictly compartmentalized processes of uridine salvage to UTP and uridine generation from UTP, in which uptaken undine is anabolised to UTP in the cytosol, and converted back to undine in extracellular space. (C) 2010 Elsevier Ltd. All rights reserved.