Diadenosine polyphosphates facilitate the evoked release of acetylcholine from rat hippocampal nerve terminals

Diadenosine polyphosphates are present in synaptic vesicles, are released upon nerve stimulation and possess membrane receptors, namely in presynaptic terminals. However, the role of diadenosine polyphosphates to control neurotransmitter release in the CNS is not known. We now show that diadenosine pentaphosphate (Ap(5)A, 3-100 microM) facilitated in a concentration dependent manner the evoked release of acetylcholine from hippocampal nerve terminals, with a maximal facilitatory effect of 116% obtained with 30 microM Ap(5)A. The selective diadenosine polyphosphate receptor antagonist, diinosine pentaphosphate (Ip(5)I, 1 microM), inhibited by 75% the facilitatory effect of Ap(5)A (30 microM), whereas the P(2) receptor antagonists, suramin (100 microM) and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 10 microM) only caused a 18-24% inhibition, the adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (20 nM), caused a 36% inhibition and the adenosine A(2A) receptor antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo [2,3-a][1,3, 5]triazin-5-ylamino]ethyl)phenol (ZM 241385, 20 nM), was devoid of effect. These results show that diadenosine polyphosphates act as neuromodulators in the CNS, facilitating the evoked release of acetylcholine mainly through activation of diadenosine polyphosphate receptors.