A NOVEL RECEPTOR FOR DIADENOSINE POLYPHOSPHATES COUPLED TO CALCIUM INCREASE IN RAT MIDBRAIN SYNAPTOSOMES

1 Diadenosine polyphosphates, Ap(4)A and Ap(5)A, as well as ATP, alpha ,beta-MeATP and ADP-beta-S, were able to elicit variable intrasynaptos omal Ca2+ increases in rat midbrain synaptic terminals. The origin of the Ca2+ increment was the extrasynaptosomal space since the eliminati on of extracellular Ca2+ abolished the effect of all the agonists. 2 T he P-2-purinoceptor antagonist, suramin, did not affect the Ca2+-incre ase evoked by diadenosine polyphosphates but dramatically blocked the Ca2+ entry induced by ATP and its synthetic analogues. 3 The actions o f Ap(5)A and ATP on the intrasynaptosomal Ca2+ increase did not cross- desensitize, 4 Concentration-response studies for diadenosine polyphos phates showed pot values of 54.5 +/- 4.2 mu M and 55.6 +/- 3.8 mu M fo r Ap(4)A and Ap(5)A, respectively. 5 The entry of calcium induced by d iadenosine polyphosphates could be separated into two components. The first represented a selective voltage-independent Ca2+ entry; the seco nd, a sustained phase which was voltage-dependent. 6 Studies on the vo ltage-dependent Ca2+-channels involved in the effects of the diadenosi ne polyphosphates, demonstrated that omega-conotoxin G-VI-A inhibited the sustained Ca2+-entry, suggesting the participation of an N-type Ca 2+-channel. This toxin was unable to, abolish the initial cation entry induced by Ap(4)A or Ap(5)A. omega-Agatoxin IV-A, tetrodotoxin, or ni fedipine did not inhibit the effects of the diadenosine polyphosphates . 7 The effect of ATP on Ca2+-entry was abolished by nifedipine and om ega-conotoxin G-VI-A, suggesting the participation of L- and N-type Ca 2+-channels in the response to ATP. 8 These data suggest that Ap(4)A, Ap(5)A and ATP activate the same intracellular Ca2+ signal through dif ferent receptors and different mechanisms. Ap(4)A and Ap(5)A induce a more selective Ca2+-entry in a voltage-independent process. This is th e first time that a selective action of diadenosine polyphosphate thro ugh receptors other than P-1 and P-2-purinoceptors has been described.