The P2Y/P2X divide: How it began.

Extracellular purine and pyrimidine nucleotides produce their pharmacological effects through P2 receptors. These were first named by Geoff Burnstock in an extensive review in 1978. They were then subdivided into P2X and P2Y purinoceptors by Burnstock and Kennedy in 1985, based on applying pharmacological criteria to data generated by functional studies in smooth muscle tissues. Several other P2 subtypes, P2T, P2Z, P2U and P2D were subsequently identified in the following years, again using pharmacological criteria. The number and identity of subtypes were clarified and simplified by the cloning of seven ATP-sensitive ligand-gated ion channel subunits and eight adenine and/or uracil nucleotide-sensitive G protein-coupled receptors from 1993 onwards. The former were all classified as members of the P2X receptor family and the latter as members of the P2Y receptor family. More recently, high resolution imaging of the tertiary and quaternary structures of several P2X and P2Y receptor subtypes has provided a much greater understanding of how and where agonists and antagonists bind to the receptors and how this leads to changes in receptor conformation and activity. In addition, medicinal chemistry has produced a variety of subtype-selective agonists and antagonists, some of which are now in clinical use. This progress and success is a testimony to the foresight, intelligence, enthusiasm and drive of Geoff Burnstock, who led the field forward throughout his scientific life.