NEW INSIGHTS ON P-2X PURINOCEPTORS

`Significant advances in understanding of P-2X purinoceptor pharmacolo gy have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated, Fortunately inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleoti de breakdown. Despite these issues, convincing evidence for P-2X recep tor heterogeneity, from data with agonists, has recently been reported . A number of new antagonists at P-2X Purinoceptors have also recently been described which to some degree appear to be more specific and us eful than earlier antagonists like suramin, It is now apparent that su ramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which i t blocks the P-2X purinoceptor. Advances in the use of radiolabelled n ucleotides as radioligands for binding studies has allowed the demonst ration of P-2X purinoceptors in a variety of tissues throughout the bo dy including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P-2X purinoceptor genes have b een cloned but operational studies suggest that more than two types ex ist. The cloning studies have also demonstrated a unique structure for the P-2X purinoceptor which differentiates it from all other ligand-g ated ion channel receptors. Further studies on P-2X purinoceptor opera tion and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide recep tors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activa tion of P-2X purinoceptors. This will require the identification of be tter drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents.