Presynaptic signal transduction pathways that modulate synaptic transmission

Presynaptic modulation is a crucial factor in the adaptive capacity of the nervous system. The coupling between incoming action potentials and neurotransmitter secretion is modulated by firstly, recent activity of the presynaptic axon that leads to the accumulation of residual calcium in the terminal and secondly, activation of presynaptic receptors by external signals. Despite the detailed description of these phenomena, the underlying mechanisms are still poorly understood. The nerve terminal contains many Ca2+-binding proteins that may contribute to the translation of residual Ca2+-increases to secretion modulation. We also found that > 100 presynaptic proteins are phosphorylated and may contribute to the translation of presynaptic receptor activation to secretion modulation. However, which of these many candidates are the dominant regulators and how their activities integrate is largely unknown. Here, we review some of the recent insights into the complex interplay between presynaptic signal transduction components and propose blueprints of the major pathways.