[S-35]CTP gamma S autoradiography reveals a wide distribution of G(i/o)-linked ADP receptors in the nervous system: close similarities with the platelet P2Y(ADP) receptor

No G(i)-linked P2Y receptors have been cloned to date but the presence of s uch receptors is thought to be restricted to platelets and certain clonal c ell lines. Using the functional approach of [S-35]guanosine 5 '-[gamma -thi o]-triphosphate autoradiography, we uncovered the widespread presence of su ch receptors in the CNS. Under conditions in which the prominent signal due to tonic adenosine receptor activity is masked, ADP and ATP stimulated G-p rotein activity in multiple grey and white matter regions. Localization in the grey matter suggests inhibitory auto-/heteroreceptor function. In the w hite matter, activated G proteins appeared as 'hot spots' (presumed oligode ndrocyte progenitors) with scattered distribution along the main fibre trac ts. Responses to ATP were diminished under conditions that inhibited degrad ation, suggesting that prior conversion to ADP explained agonist action. Ur acil nucleotides were ineffective but 2-methylthio-ADP activated G proteins approximate to 500-fold more potently than ADP, although both were similar ly degraded. Throughout the brain, ADP-dependent G-protein activity was rev ersed by 2-hexylthio-AdoOC(O)Asp(2), a non-phosphate ATP analogue, whereas selective P2Y(1) receptor antagonists proved ineffective. A similar recepto r was also disclosed from the adrenal medulla. These data witness a hithert o unrecognized abundance of G(i/O)-linked ADP receptors in the nervous syst em. Biochemical and pharmacological behaviour suggests striking similaritie s to the elusive platelet P2Y(ADP) receptor.