Fig. 1. Presynaptic ER Ca²⁺ stores.

Presynaptic terminal is filled with synaptic vesicles (SVs). Canonical evoked neurotransmission is driven by Ca²⁺ influx through voltage gated Ca²⁺ channels (VGCCs). Smooth ER is present in many presynpatic terminals. Ca²⁺ release from ER is mediated by ryanodine receptors (RyR) by a mechanism of Ca²⁺-induced Ca²⁺ release (CICR). ER Ca²⁺ depletion causes clustering of STIM1 Ca²⁺ sensor protein and activation of store-operated Ca²⁺ entry pathway (SOCE) via Ca²⁺ influx through Orai channels. There is increasing evidence that both CICR and SOCE can impact neurotransmitter release.