SLOW DESENSITIZATION OF THE HUMAN P2Y(6) RECEPTOR

The P2Y(6) receptor is a recently cloned P-2 receptor which displays a high sensitivity for diphosphonucleotides. In 1321N1 astrocytoma cell s stably expressing this receptor, UDP induced a slow and sustained ac cumulation of inositol trisphosphate via a pertussis toxin-insensitive G-protein: the maximal level was only reached after 15 min and a sign ificant response was maintained for at least 3 h. A full second respon se to UDP was obtained after the first 45-min stimulation but was lost after 165 min. This slow and sustained time-course and the lack of de sensitization was reproduced with ADP. UTP was unable to restimulate t he P2Y(4) receptor, another recently cloned P-2 receptor with a prefer ence for UTP, after the first 5-min stimulation. The P2Y(4) receptor i s thus rapidly desensitized whereas desensitization of the P2Y(6) rece ptor is delayed. The rank order of potency of various diphosphonucleot ides at the P2Y(6) receptor was: UDP > TDP > IDP > GDP > ADP >> CDP. T he activity of three non-specific antagonists of P-2 receptors was cha racterized by the following rank order of potency: reactive blue 2 > p yridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS)> suramin . In conclusion, the most impressive features of the human P2Y(6) rece ptor revealed by this study are the slow and sustained time-course of its activation and its. high resistance to desensitization. (C) 1997 E lsevier Science B.V.