Neuroprotection elicited by P2Y13 receptors against genotoxic stress by inducing DUSP2 expression and MAPK signaling recovery

Abstract

Nucleotides activating P2Y13 receptors display neuroprotective actions against different apoptotic stimuli in cerebellar granule neurons. In the present study, P2Y13 neuroprotection was analyzed in conditions of genotoxic stress. Exposure to cisplatin and UV radiation induced caspase-3-dependent apoptotic cell death, and p38 MAPK signaling de-regulation. Pre-treatment with P2Y13 nucleotide agonist, 2methyl-thio-ADP (2MeSADP), restored granule neuron survival and prevented p38 long-lasting activation induced by cytotoxic treatments. Microarray gene expression analysis in 2MeSADP-stimulated cells revealed over-representation of genes related to protein phosphatase activity. Among them, dual-specificity phosphatase-2, DUSP2, was validated as a transcriptional target for P2Y13 receptors by QPCR. This effect could explain 2MeSADP ability to dephosphorylate a DUSP2 substrate, p38, reestablishing the inactive form. In addition, cisplatin-induced p38 sustained activation correlated perfectly with progressive reduction in DUSP2 expression. In conclusion, P2Y13 receptors regulate DUSP2 expression and contribute to p38 signaling homeostasis and survival in granule neurons.

Neuroprotection Mediated by P2Y 13 Nucleotide Receptors in Neurons

“…As expected, dusp2 expression was abolished by the inhibition of both ERK signaling and PI3K activity, and by the P2Y 13 specific antagonist MRS2211. These data confirmed that dusp2 gene was under the regulation of PI3K/ERK1/2 mediated signaling stimulated by P2Y 13 receptors in granule neurons [43].…”

“…As expected, P2Y 13 receptor-mediated dephosphorylating effect on p38 as well as its prosurvival actions during cisplatin treatment were prevented by both P2Y 13 specific antagonist MRS2211 and the inhibitor of tyrosine phosphatases orthovanadate. Therefore, P2Y 13 activity on DUSP2 expression also contributed to neuroprotection against genotoxic stress [43] (Fig. 5).…”

Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug‐refractory epilepsy

“…We have now extended these data, showing no significant changes for the remaining receptors in a TLE patient cohort, with the only exception being P2Y 13 displaying lower levels. Of interest, P2Y 13 activation has been shown to exert neuroprotective effects in vitro; therefore, the reduction in P2Y 13 levels could contribute to increased vulnerability to seizure‐induced neurodegeneration. We did observe some differences between our mouse model of epilepsy and the TLE patient brain.…”

An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration

“…P2Y 1 receptor antagonists improve recovery from traumatic brain injury (Choo et al, 2013). A recent paper reports that neuroprotection against genotoxic stress is elicited by P2Y 13 receptor activation (Morente et al, 2014). The P2Y-like receptor, GPR17, is a sensor of brain damage and reacts to the release of nucleotides and cysteinyl leukotrienes in a focal ischaemia model (Lecca et al, 2008).…”