**3.3 Physiological relevance (bursting, behavior, etc.)**

Magnocellular neurons in the supraoptic (SON) and paraventricular (PVN) nuclei (see **Figure 2**) exhibit bursting patterns leading to secretion of oxytocin in a characteristic episodic or pulsatile manner rather than in a continuous or steady stream [13, 32, 33]. The bursting pattern is regulated by various physiological and environmental factors, such as sensory stimuli, including touch, suckling, and sexual activity. These stimuli activate specific brain regions, leading to increased activity in oxytocin

#### **Figure 2.**

*The diagram of hypothalamic neurohypophysial system (HNS) showing cell bodies in hypothalamic supraoptic (SON) and paraventricular nuclei (PVN) projecting to terminals in neurohypophysis and in central nervous system (CNS) [22, 30, 31]. The priming of release takes place via IP3R (inositol triphosphate (IP3) receptors) in oxytocin (OT) cell bodies but via RyR (ryanodine receptors) in OT terminals.*

#### *Modulation of Oxytocin Release by Internal Calcium Stores DOI: http://dx.doi.org/10.5772/intechopen.112630*

neurons and subsequent bursts of oxytocin release [34]. The bursting pattern of oxytocin secretion is particularly relevant during reproductive processes, including childbirth, breastfeeding, and bonding between individuals [35–37].

The episodic nature of oxytocin release allows for precise and selective activation of oxytocin receptors, ensuring proper physiological responses. The precision of these responses highlights the importance of linking OT release with appropriate physiological and environmental signaling. The pattern of the electrical activity of OT neurons exhibits a sustained outwardly rectifying potential, as well as a consequent depolarizing rebound potential, not found in AVP neurons [38]. OT neurons further exhibit specific voltage-gated calcium channels, R-type, which are modulated by distinct pathways not associated with AVP neurons [39, 40]. Furthermore, in OT neurons, but not in AVP, the activity and modulation of release are highly dependent on the presence of the second messenger, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) [41], which permissively gates N-type channels that contribute to the Ca2+ influx during spike trains [42] and mediates positive feedback via activation of OT receptors (OTRs) (**Figure 2**) within the dendritic arborization of cell bodies in SON and PVN [43, 44].

The oxytocin receptor and inositol trisphosphate (IP3) are interconnected in a signaling pathway that mediates the effects of oxytocin on cellular responses. When oxytocin binds to its receptor, it leads to the activation of a G protein associated with the receptor. This activation causes the G protein to exchange GDP (guanosine diphosphate) for GTP (guanosine triphosphate), leading to the dissociation of the G protein into its α, β, and γ subunits [45]. The α subunit of the G protein then activates phospholipase C (PLC) activating a cascade of intracellular events, including the generation of IP3. The IP3 messenger acts as a diffusible molecule that binds to IP3 receptors (IP3Rs) located on the endoplasmic reticulum (ER) membrane in OT neuronal cell bodies releasing calcium ions (Ca2+) from the ER stores into the cytoplasm. This increase in intracellular calcium concentration triggers various cellular responses, including modulation of synaptic transmission in the brain. Notably, so far, the presence of endoplasmic reticulum and subsequent IP3 signaling has not been observed in neurohypophysial terminals. It is worth noting that the interactions between oxytocin receptor signaling and IP3 are just one aspect of the broader mechanisms underlying intercellular calcium stores and oxytocin's physiological effects. Having shown that DSC occurs in the absence of extracellular Ca2+ and is independent of VGCCs lends support to the general premise of the Ca2+-voltage hypothesis of Parnas and colleagues [46]. Whether this process modulates or plays a key role in the initiation and/ or the termination of physiological release during a burst of action potentials in the HNS, however, remains to be proven.
