Neuroprotection Mediated by P2Y 13 Nucleotide Receptors in Neurons

Abstract

ADP-specific P2Y13 receptor constitutes one of the most recently identified nucleotide receptor and the understanding of their physiological role is currently under investigation. Cerebellar astrocytes and granule neurons provide excellent models to study P2Y13 expression and function since the first identification of ADP-evoked calcium responses not attributable to the related P2Y1 receptor was performed in these cell populations. In this regard, all responses induced by ADP analogues in astrocytes resulted to be Gi-coupled activities mediated by P2Y13 instead of P2Y1 receptors. Similarly, both glycogen synthase kinase-3 (GSK3) and ERK1/2 signaling triggered by 2MeSADP in cerebellar granule neurons were also dependent on Gi-coupled receptors, and mediated by PI3K activity. In granule neurons, P2Y13 receptor was specifically coupled to the main neuronal survival PI3K/Akt-cascade targeting GSK3 phosphorylation. GSK3 inhibition led to nuclear translocation of transcriptional targets, including β-catenin and Nrf2. The activation of the Nrf2/heme oxygenase-1 (HO-1) axis was responsible for the prosurvival effect against oxidative stress. In addition, P2Y13-mediated ERK1/2 signaling in granule neurons also triggered activation of transcription factors, such as CREB, which underlined the antiapoptotic action against glutamate-induced excitotoxicity. Finally, a novel signaling mechanism has been recently described for a P2Y13 receptor in granule neurons that involved the expression of a dual protein phosphatase, DUSP2. This activity contributed to regulate MAPK activation after genotoxic stress. In conclusion, P2Y13 receptors harbored in cerebellar astrocytes and granule neurons exhibit specific signaling properties that link them to specialized functions at the level of neuroprotection and trophic activity in both cerebellar cell populations.

Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis

“…Another novel finding presented herein is the significant up-regulation of P2Y 13 receptor at Er , indicating that the induction of this P2 purinoceptor may be associated with the resolution of neuroinflammation and a recovery from the disease. The suggestions are corroborated by findings that the activation of P2Y 13 receptor induces main pro-survival pathways in neurons, such as ERK1/2 and PI3K/Akt/GSK3 (Pérez-Sen et al, 2015 ), which are normally activated by trophic factors, and the activation of the Nrf2/HO-1 axis which protects from excitotoxic damage (Espada et al, 2010 ). These findings link ADP to neuroprotection and imply that, in contrast to ATP, ADP may promote survival and increased neuronal resistance to different insults (del Puerto et al, 2012 ).…”

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…P2Y 1 , P2Y 2 and P2Y 13 receptors are also present in neurons. P2Y 1 and P2Y 13 receptors together with the ionotrotropic P2X7 receptors regulate neuronal differentiation and are also involved in neuroprotection and neurodegeneration (Miras Portugal et al, 2019; Perez‐Sen et al, 2015). Some P2Y receptors ‐ P2Y 1 , P2Y 2 , and P2Y 4 ‐ appear to be up‐regulated in pathological conditions such as brain injury, Alzheimer's disease, and epilepsy (Franke et al, 2012).…”

Purinergic Signalling: Therapeutic Developments

“…From a recent study on P2Y 2 R knockout (KO) mice and murine cell lines, it was concluded that P2Y 2 R play a neuroprotective role in neurological disorders, especially AD ( de Diego-Garcia et al, 2017 ). Neuroprotection is claimed to be mediated by P2Y 13 nucleotide receptors in neurons ( Pérez-Sen et al, 2015 ). Activation of P2Y 2 R evokes regeneration of glial cells and nerves and the P2YR-like GPR17 evokes oligodendrocyte regeneration.…”