Molecular machinery for Ca²⁺ signal formation in hepatocytes. Ca²⁺ signals may be generated by Ca²⁺‐mobilizing hormones (through activation of G‐protein‐coupled receptors) or growth factors (through receptor tyrosine kinases). Binding of a ligand to its specific receptor leads to the activation of phospholipase C (PLC), which hydrolyzes Phosphotidylinositol‐4‐5‐bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5‐trisphosphate (InsP3). DAG remains in the plasma membrane and InsP3 diffuses throughout the cytosol and binds to the InsP3 receptor (InsP3R) in the endoplasmic reticulum to allow Ca²⁺ release to the cytosol. Alternatively, receptor tyrosine kinases may translocate to the nucleus to locally activate PLC and induce Ca²⁺ release from the nucleoplasmic reticulum into the nucleoplasm. Nuclear PIP2 is depicted. However, its exact localization within the nucleus remains unknown [modified from references (212) and (137), with permission].

Physiological and pathophysiological actions of Ca²⁺ in hepatocytes. 1. Cytosolic and mitochondrial Ca²⁺ signals are closely interrelated. Ca²⁺ is transmitted from inositol 1,4,5‐trisphosphate receptors (InsP3Rs) to mitochondria, leading to an increase in mitochondrial free Ca²⁺ and the formation of the permeability transition pore (PTP). Reversible opening of the PTP is observed in normal mitochondrial function and shapes Ca²⁺ signals, but persistent opening of the PTP leads to leakage of cytochrome c, augmenting the cellular sensitivity to apoptotic stimuli. 2. Type II InsP3R‐mediated Ca²⁺ release regulates organic anion and bile salt secretion through the insertion of the transporters multidrug resistance‐associated protein 2 (MRP2) and bile salt export pump (BSEP), respectively, into the canalicular membrane. Loss of this isoform results in impaired transporter activity and contributes to the pathophysiology of intrahepatic cholestasis. 3. Nuclear Ca²⁺ is essential for cell‐cycle progression through the control of gene transcription and expression of proliferative proteins. Furthermore, nuclear Ca²⁺ may be associated with liver tumor growth. 4. The endoplasmic reticulum (ER) regulates protein folding, quality control, trafficking, and targeting, and these depend on adequate amounts of Ca²⁺ in the ER lumen. Unbalance between ER load and protein‐folding capacity leads to ER stress. In obesity, liver expression and activity of SERCA are impaired, leading to ER stress and defective glucose metabolism.

Ca²⁺ waves begin in the apical region of hepatocytes. (A) Confocal images of an isolated rat hepatocyte couplet loaded with the Ca²⁺ sensitive dye Fluo‐4/AM and stimulated with vasopressin. Serial images of the region of interest outlined in yellow show that a Ca²⁺ wave starts in the apical (a) region of the cell and spreads to the basolateral (b) region. Images were pseudocolored according to the scale shown at the bottom. (B) Graphical representation of the fluorescence increase in the apical and basolateral region shows that the apical Ca²⁺ signal precedes the basolateral Ca²⁺ signal [modified from reference (264), with permission].

Inositol 1,4,5‐trisphosphate receptors (InsP3R) expression is lost in bile duct epithelia after bile duct ligation. Confocal immunofluorescence of liver sections from normal rats and rats subjected to bile duct ligation (BDL) labeled with isoform‐specific InsP3R antibodies (green) and rhodamine phalloidin (red). Type 1 InsP3R labeling in normal bile duct cells (A) is found throughout each cell although is expressed at low levels, similar to that observed 2 weeks after BDL (B). Type 2 InsP3R labeling is seen throughout each cell in normal liver sections (C) and it is nearly absent 2 weeks after BDL (D). Type 3 InsP3R labeling is found predominantly in the apical region of bile duct cells in normal liver sections (E) and is also markedly reduced 2 weeks after BDL (F) [reprinted from reference (356), with permission].