Leukocyte P2 Receptors: A Novel Target for Anti-inflammatory and Antitumor Therapy
Current Drug Targets - Cardiovascular & Hematological Disorders
P2 receptors are a class of plasma membrane receptors ligated by extracellular nucleotides and expressed ubiquitously throughout the body. Two main families are known: P2X and P2Y. P2X are ligand (ATP)-gated channels, while P2Y are G-protein-coupled seven membrane-spanning receptors. The P2X and the P2Y subfamilies comprise seven and eight members, respectively. While ATP is the only known physiological ligand of P2X receptors, P2Y receptors are known to be also activated by ADP, UTP, UDP and
... ADP, UTP, UDP and UDP-glucose in a subtype-specific manner. Several P2 subtypes are expressed by leukocytes where they have been implicated in a host of different responses ranging from chemotaxis to differentiation, from proliferation to cytotoxicity, from secretion of inflammatory mediators to cell fusion. However, until recently there was no in vivo proof of the participation of P2 receptors in inflammatory or proliferative disorders and, in addition, few pharmacological modulators of P2 function were available. During the last two years animal and human studies have produced preliminary but nevertheless compelling evidence in support of an important function of P2 receptors in inflammation and hematological tumors. Importantly, selective blockers of these receptors have been synthesized, thus paving the way to the possible development of P2-targeted anti-inflammatory and anti-tumoral therapies. P2 RECEPTOR SUBFAMILIES P2 receptors (P2R) transduce signals carried by extracellular nucleotides. According to the most recent nomenclature of IUPHAR (International Union of Pharmacology), they are classified into P2Y and P2X. P2Y receptors (P2YR), also referred to as "metabotropic", are coupled via G-proteins to changes in intracellular Ca 2+ ([Ca 2+ ] i ) homeostasis and/or cAMP concentration  . P2XR, also referred to as "ionotropic", are poorly selective cation channels made by the assembly of the same (homo-oligomers) or different (hetero-oligomers) subunits. Thus far, seven P2X subunits have been cloned [22, 23] . The main signal-transducing system activated by P2XR stimulation involves changes in the intracellular cation concentration, but other pathways have also been identified recently [24, 25] .