Purinergic P2X receptors: physiological and pathological roles and potential as therapeutic targets

P2X receptors for extracellular ATP (P2Xs) are widely distributed ion channels that mediate several processes like neurotransmission, neuromodulation, inflammation, pain sensing, cell proliferation and differentiation. Targeting of P2X receptors by specific modulators has been suggested for a variety of possible therapeutic applications like the treatment of inflammatory, neurological and neurodegenerative diseases, cardiovascular, bone, renal and endocrine disorders, pain and cancer. Purpose of this special issue is to offer a comprehensive overview on P2X receptors considering their structural and functional features, agonist and antagonist ligands, physio-pathological roles, and their potential as therapeutic targets. A review from the founding father of the purinergic field Burnstock opens the issue and gives an overview of the early findings on purinergic signaling, focusing on the roles of P2X receptors in the central nervous system. Functions of P2X receptors in physiological and pathological conditions involving CNS are also brilliantly covered. Another wide-ranging manuscript is that of Di Virgilio on the role of P2X receptors in inflammation. This is an overview of P2Xs roles in danger sensing, inflammasome activation and release of inflammatory mediators. The contributions to this special issue by Grimes & Young and Hausmann et al. offer an introduction of the structural properties of P2X receptors observed from X-ray data and modeling studies and provide information about trimer stoichiometry and ligand-target interaction coming from mutagenesis studies results. The reviews from Müller and Lambertucci et al. provide a description of the different classes of P2X ligands working with allosteric or orthosteric mechanism, respectively, giving information about compound selectivity and therapeutic potential. Bele & Fabbretti report on the role of P2Xs on pain transmission and on the potential of targeting P2X for novel analgesic drugs. Similarly, the paper from Ralevic focusses on P2X function in the cardiovascular system and vascular smooth muscle contraction, highlighting the function of P2Xs in the regulation of blood pressure. In their manuscript, Fotino et al. give an overview of P2X and ATP signaling in the pathogenesis of diabetes and its complications. The authors discuss the role of P2Xs in insulin secretion and diabetes associated metabolic alterations. The role of P2X receptors on bone biology is described by Jorgensen et al. who give an overview on data derived from P2X null mice and analysis of receptor’s SNPs in bone-associated diseases. Finally, the paper by Adinolfi et al. focusses on the role of P2X receptors in cancer, addressing tumoral growth, progression and related symptoms. All papers suggest the use of P2X ligands as therapeutics in a wide-range of pathologies. We are grateful to all the authors for their kind participation and valuable contribution and hope that this issue could represent, for the scientific community, a solid basis for further studies on P2X receptors and the development of P2X targeting therapeutic tools