Emerging Mechanisms in Purinergic Signaling: from Cell Biology to Therapeutic Perspectives

Extracellular ATP (adenosine 5’-triphosphate) and adenosine represent relevant signaling molecules whose effect is tightly controlled by a significant number of membrane receptors, ectoenzymes and transporters, all together comprising the so-called Purinome. Purinergic signaling was proposed in 1972, and despite an early resistance to the concept, it was generally accepted in the early 1990’s when purinergic receptors were cloned and characterized, producing an explosion of interest in the physiology and pathophysiology of these nucleotidic compounds in the last decades. Purinergic receptors include four subtypes of P1 metabotropic receptors for adenosine, seven subtypes of P2X ATP-gated ion channels, and eight subtypes of P2Y G protein-coupled receptors for ATP and other nucleotides. Extracellular signaling mediated by nucleotides is regulated by ectonucleotidases, a wide family of metallo-ectoenzymes involved in the breakdown of released ATP into ADP, AMP, and adenosine, hence modulating P1- and P2-receptor-mediated signaling. Purinergic receptors and ectonucleotidases, such as CD39 and CD73, have been investigated in relation to a wide variety of pathologies, including neurodegenerative and neurological disorders, cardiovascular, skeletal, reproductive and immune system diseases, as well as alterations sense organs, airways, skin, muscles, gut, kidney and urinary tract. They also participate in the control of neuropathic/inflammatory pain and tumorigenesis. Potent and selective agonists/antagonists, allosteric modulators and blocking antibodies of most purinergic receptors and ectonucleotidases are currently available, and a number of purine-related compounds have been clinically proved and patented. Among them, Clopidogrel, Prasugrel and Ticagrelor, all targeting the platelet P2Y12 receptor, are among the best-selling anti-thrombotic drugs. Moreover, clinical trials are currently in progress to explore purinergic agents for the treatment of several diseases such as osteoporosis, visceral pain, cancer and neurodegenerative diseases.

The contributions proposed for this Research Topic will discuss the current state of art on the role of purinergic signaling in both physiological and pathological circumstances. This Research Topic will also cover original research focusing on purinergic receptors, ectonucleotidases and nucleoside/nucleotide transporters. Both review and research papers will be considered for publication. This may help define a new baseline for discovery and novel therapies to come.