Cerebellar granule neurons express several types of nucleotide receptors, with the metabotropic P2Y₁₃ and the ionotropic P2X7 being the most relevant in this model. In the present study we investigated the role of P2Y₁₃ and P2X7 nucleotide receptors in ERK1/2 signalling. The nucleotidic agonists 2MeSADP (2-methylthioadenosine-5′-diphosphate) for P2Y₁₃ and BzATP (2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate) for P2X7 receptors were coupled to ERK1/2 activation in granule neurons, being able to increase around two-fold the levels of ERK1/2 phosphorylation. These effects were sensitive to the inhibitory action of the antagonists MRS-2211 and A-438079, specific for P2Y₁₃ and P2X7 receptors, respectively. Although both receptor subtypes shared the same pattern of transient ERK1/2 phosphorylation, they differed in the intracellular cascades they triggered, being PI3K-dependent for P2Y₁₃ and calcium/calmodulin kinase II (CaMKII)-dependent for P2X7. These two different ERK-mediated pathways were involved in the neuroprotective effects displayed by both P2Y₁₃ and P2X7 receptors against apoptosis induced by an excitotoxic concentration of glutamate, in a similar manner to the neurotrophin, BDNF. In addition, P2Y₁₃ and P2X7 receptor agonists were also able to phosphorylate and activate the ERK-dependent target CREB, which could be involved in their neuroprotective effect. These results indicate that nucleotide receptors share with trophic factors the same survival routes in neurons, such as the ERK signalling route, and therefore, can contribute to the maintenance of granule neurons in conditions in which survival is being compromised.