Ryanodine receptor modulation by diadenosine polyphosphates in synaptosomal and microsomal preparations of rat brain

Diadenosine polyphosphates (Ap(n)As) are transmitter-like substances that act intracellularly via unclear mechanisms. Here we tested hypotheses that diadenosine tetraphosphate (Ap(4)A) modulates ryanodine binding in microsomal and synaptosomal fractions of rat brain, and that Ap(4)A affects modulation of ryanodine binding by divalent cations and caffeine. Using [3H]ryanodine-binding assays, we showed that Ap(4)A produced significant and concentration-dependent increases in [3H]ryanodine binding in microsomes and these actions were reduced by Mg(2+) and potentiated by caffeine. In synaptosomal subfractions, effects of Ap(4)A on [3H]ryanodine binding were most profound in subfractions enriched in synaptic vesicle-associated protein synaptophysin. These results suggest that Ap(n)As and ryanodine receptors are well placed to modulate Ca(2+)-dependent synaptic processes.