Rethinking purinergic concepts and updating the emerging role of P2X7 and P2X4 in amyotrophic lateral sclerosis

The topic of the present review regards the ubiquitous and phylogenetically most ancient prototype of intercellular signaling, the one mediated by extracellular nucleosides and nucleotides, bearing a strong influence on pathophysiological processes in the nervous system. Not by chance, purine and pyrimidine molecules are the most prevalent and ubiquitous chemical messengers in the animal and plant kingdoms, operating through a large plethora of purinergic metabolizing enzymes, P1 and P2 receptors, nucleoside and nucleotide channels and transporters. Because ectonucleotidases degrade the agonists of P2 receptors while simultaneously generate the agonists for P1 receptors, and because several agonists, or antagonists, simultaneously bind and activate, or inhibit, more than one receptor subtype, it follows that an all-inclusive "purinergic network" perspective should be better considered when looking at purinergic actions. This becomes particularly crucial during pathological conditions as for instance amyotrophic lateral sclerosis, where the contribution of purinergic signaling has been demonstrated to differ according to each target cell phenotype and stage of disease progression. Here we will present some newly updated results about P2X7 and P2X4 as the most thoroughly investigated P2 receptors in amyotrophic lateral sclerosis, being aware that the comprehension of their actions is still in progress, and that the purinergic rationale for studying this disease must be however wide-ranging and all-inclusive.