Involvement of Uridine-Nucleotide-Stimulated P2Y Receptors in Neuronal Growth and Function

The uridine nucleotides UTP, UDP and UDP-sugars produce a variety of effects by activating specific G protein- coupled P2Y receptors, i.e., the P2Y2, P2Y4, P2Y6 and P2Y14 variants. Except for P2Y14 which has recently been defined, stimulation of P2Y receptors by UTP and/or UDP augments proliferation of adult multipotent neural stem cells; stimulates dopaminergic differentiation in human mesencephalic neural stem cells; and enhances neurite outgrowth in nerve growth factor-differentiated PC12 cells and cultured DRG neurons. UTP and/or UDP have been shown to affect neuronal function by depolarizing neurons from cultured amphibian sympathetic ganglia; increasing firing rates of neurons; enhancing presynaptic glutamate release and promoting long-term potentiation; and by stimulating noradrenaline release from cultured sympathetic neurons. Furthermore, by activating P2Y receptors, UTP and/or UDP exhibit neuroprotective effects via induction of microglial convergence and reactive astrogliosis; protection from serum starvation-induced apoptosis; and stimulation of α-secretase-dependent APP processing and sAPPα release. Antagonism of uridine- nucleotide- stimulated P2Y receptors or the second messengers they generate, or degradation of extracellular uridine nucleotides, can block the effects mediated by these receptors. These observations suggest that uridine-nucleotide-stimulated P2Y receptors may constitute possible therapeutic targets for diseases affecting neuronal survival or function.