Synaptic efficacy is remodeled by neuronal firing activity at the presynaptic terminal. Presynaptic activity-dependent changes in transmitter release induce postsynaptic plasticity, including morphological change in spine, gene transcription, and protein synthesis and trafficking. The presynaptic transmitter release is triggered and regulated by Ca(2+), which enters through voltage-gated Ca(2+) (Ca(V)) channels and diffuses into the presynaptic terminal accompanying action potential firings. Residual Ca(2+) is sensed by Ca(2+)-binding proteins, among other potential actions, it mediates time- and space-dependent synaptic facilitation and depression via effects on Ca(V)2 channel gating and vesicle replenishment in the readily releasable pool (RRP). Calmodulin, a Ca(2+)-sensor protein with an EF-hand motif that binds Ca(2+), interacts with Ca(V)2 channels and autoreceptors in modulation of SNARE-mediated exocytosis.