Recent studies have begun to scrutinize the presynaptic machinery and vesicle populations that give rise to action potential evoked and spontaneous forms of neurotransmitter release. In several cases this work produced unexpected results which lend support to the notion that regulation, mechanisms, postsynaptic targets and possibly presynaptic origins of evoked and spontaneous neurotransmitter release differ. Furthermore, the list of regulatory pathways that impact spontaneous and evoked release in a divergent manner is rapidly growing. These findings challenge our classical views on the relationship between evoked and spontaneous neurotransmission. In contrast to the well-characterized neuromodulatory pathways that equally suppress or augment all forms of neurotransmitter release, molecular substrates specifically controlling spontaneous release remain unclear. In this review, we outline possible mechanisms that may underlie the differential regulation of distinct forms of neurotransmission and help demultiplex complex neuronal signals and generate parallel signaling events at their postsynaptic targets.
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