{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSynaptotagmin IV (Syt IV; also termed Synaptotagmin-4 in some studies) emerges as a critical modulator of Ca²⁺‐dependent exocytosis in the central nervous system. In hippocampal neurons and astrocytes, Syt IV regulates neurotransmitter release and gliotransmission—its expression in astrocytes is essential for calcium‐dependent glutamate exocytosis and proper hippocampus-dependent memory, while its postsynaptic localization also governs the targeted release of neurotrophins like BDNF to scale synaptic strength and control long‐term potentiation. These studies implicate Syt IV as a negative regulator of short-term plasticity and reveal its role in maintaining homeostatic synaptic activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in conventional synaptic release, Syt IV modulates exocytotic behavior in specialized sensory and neuroendocrine cells. In cochlear inner hair cells, its expression is necessary for establishing a linear dependence of neurotransmitter release on Ca²⁺ influx, contrasting with the higher-order calcium sensitivity mediated by other synaptotagmins. In neuroendocrine and dopaminergic systems, Syt IV influences fusion kinetics, fusion pore properties, and even the spatial aspects of synaptically targeted cargo such as dense-core vesicles, thereby affecting processes such as oxytocin/vasopressin secretion and somatodendritic dopamine release. Complementary ultrastructural studies further suggest that loss of Syt IV perturbs vesicle docking and axonal transport, underscoring its importance for coordinated presynaptic function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its neural and sensory functions, Syt IV (or Syt4) plays pivotal roles in non-neuronal secretory cells. In pancreatic β cells, for instance, a developmental upregulation of Syt4 refines insulin secretion by modulating the readily releasable pool of vesicles, thereby contributing to proper glucose-stimulated insulin secretion and β cell maturation. Similarly, in melanocytes, overexpression of Syt4 facilitates Ca²⁺ influx through the TRPM1 channel, which in turn modulates dendrite extension and melanogenesis via pathways involving ERK, CREB, and key melanogenic regulatory proteins. These findings highlight a broader functional spectrum in which Syt IV/Syt4 governs the calcium sensitivity of vesicle fusion events across diverse cell types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qi Zhang, Mitsunori Fukuda, Elisabeth Van Bockstaele, et al. 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