**2. Intraterminal [Ca2+]i stores**

When oxytocin neurons in the hypothalamus are activated, the depolarization of these neurons leads to the opening of voltage-gated calcium channels (VGCCs) followed by a Ca2+ influx through the plasma membrane. This influx of calcium ions triggers a series of events that result in the release of oxytocin both from the dendrites surrounding the cell bodies and the axonal terminals located in the neurohypophysis/ posterior pituitary. However, internal calcium stores play a crucial role in maintaining calcium homeostasis and regulating calcium signaling within the oxytocin HNS neurons. The ER is responsible for sequestering and storing calcium ions, which are released upon feedback stimulation in the cell bodies via activation of IP3R (inositol triphosphate receptors). Less is known about the accumulation of Ca2+ in the neurohypophysial granules themselves, which, when released, play a significant role in modulating OT secretion from terminals. Research has shown that an increase in intracellular calcium concentration acts as a signal for the secretory granules containing oxytocin to undergo "priming" characterized by the mobilization of granules from the releasable pool to the readily releasable and subsequently, the immediately releasable pool.

Once granules are trafficked to the immediately releasable pool, calcium influx via VGCC binds to specific proteins, such as the synaptotagmin/SNARE complex, which facilitates the fusion of the secretory granules with the plasma membrane (**Figure 1**). This fusion allows the release of oxytocin into the extracellular space, where it can act on target tissues and receptors. Calcium stores within terminals are activated by three known mechanisms: calcium-induced calcium release (CICR), depolarization via a direct link of ryanodine receptor (RyR) and L-type VGCC, and ligand-mediated G-protein receptors leading to the activation of specific signaling cascades. CICR is an essential step in the amplification of the calcium signal eliciting further release from IP3 and RyR-mediated internal stores while inactivating specific VGCC. Activation of the IP3R and RyR via calcium or by second messengers, such as IP3 or cyclic adenosine diphosphate ribose (cADPr), leads to the release of further calcium into the cytoplasm. Therefore, while calcium is key to triggering the process of secretion, the source of calcium necessary for fine-tuned depolarization-induced OT release comes from multiple sources that interact to optimize release.
