Disruption of compartmentalized calcium signaling via inositol 1,4,5-trisphosphate receptors (ITPRs) and gap junctions in primary liver cancer

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Maintaining epithelial cell polarity is a crucial defense against neoplastic progression, ensuring precise spatial and temporal organization of signals. Central to this structural and functional integrity is the compartmentalization of Ca 2+ signaling at both intracellular and intercellular levels. The most direct form of intercellular Ca 2+ propagation is mediated by gap junction channels (GJs). Their precursors, unopposed hemichannels (HCs), have been recognized for connecting the intracellular and extracellular environments, allowing the passage of a diverse range of small molecules. Although the precise molecular signals that govern specific cellular outcomes in intercellular communication have yet to be fully elucidated, inositol 1,4,5-trisphosphate (InsP3) and Ca 2+ play crucial roles as mediators of intercellular communication through GJs. Intracellular Ca 2+ release is primarily mediated by specialized release channels, specifically inositol 1,4,5-trisphosphate receptors (ITPRs), which are the predominant release pathways in polarized liver epithelial cells. In the liver, ITPRs isoforms 2 and 3 are specifically targeted to the apical membranes of hepatocytes and cholangiocytes, respectively. Under physiological conditions, Ca 2+ signaling is restricted to sub-apical trigger zones to regulate critical cellular functions, most notably, secretion. However, the transition to a pathological state is characterized by the collapse of apical signaling microdomains. Loss of ITPRs apical polarity leads to a shift from compartmentalized signaling to generalized dysregulation and GJs instability. This review synthesizes the current evidence on how the spatial organization of the ITPRs and GJs axis maintains homeostasis and how its breakdown facilitates the progression of liver malignancies.