cAMP modulates intracellular Ca2+ sensitivity of fast-releasing synaptic vesicles at the calyx of Held synapse

cAMP potentiates neurotransmitter release from the presynaptic terminal in many CNS synapses, but the underlying mechanisms remain unclear. Here we addressed this issue quantitatively by performing double patch-clamp recordings from the pre- and postsynaptic compartments of the calyx of Held synapse in rat brain stem slices in combination with Ca(2+) uncaging. We found that elevation of cAMP increased intracellular Ca(2+) sensitivity for transmitter release especially at lower Ca(2+) concentrations. The change in Ca(2+) sensitivity was limited to the fast-releasing synaptic vesicles, which could be released rapidly on action potentials. cAMP did not affect the slowly releasing vesicles. Fit of the data using a simplified allosteric model indicated that cAMP increased the fusion "willingness," thereby facilitating transmitter release. We suggest that synaptic vesicles have to be positionally primed to the release sites close to the Ca(2+) channel cluster for cAMP to modulate intracellular Ca(2+) sensitivity of transmitter release.