Calcium Signaling in Cholangiocytes: Methods, Mechanisms, and Effects

Abstract

Calcium (Ca²⁺) is a versatile second messenger that regulates a number of cellular processes in virtually every type of cell. The inositol 1,4,5-trisphosphate receptor (ITPR) is the only intracellular Ca²⁺ release channel in cholangiocytes, and is therefore responsible for Ca²⁺-mediated processes in these cells. This review will discuss the machinery responsible for Ca²⁺ signals in these cells, as well as experimental models used to investigate cholangiocyte Ca²⁺ signaling. We will also discuss the role of Ca²⁺ in the normal and abnormal regulation of secretion and apoptosis in cholangiocytes, two of the best characterized processes mediated by Ca²⁺ in this cell type.

Keywords: Ca2+; biliary tree; cholangiocytes; inositol 1,4,5-trisphosphate (InsP3); inositol 1,4,5-trisphosphate receptors (ITPRs); secretion.

Figure 1

Regulation of bicarbonate secretion in cholangiocytes. Separate signaling pathways that regulate secretion have been identified in large and small cholangiocytes. In large cholangiocytes, secretin receptors (SRs) on the basolateral membrane link to formation of cAMP, which leads to the activation of cystic fibrosis transmembrane conductance regulators (CFTRs), causing apical Cl⁻ efflux. This also stimulates exocytic release of ATP into the ductular lumen, through a mechanism that has not yet been identified. Luminal ATP then binds to apical P2Y receptors to stimulate intracellular Ca²⁺ release via inositol 1,4,5-trisphosphate receptor isoform 3 (ITPR3), which in turn activates Cl⁻ secretion through TMEM16A in the apical membrane. The resulting Cl⁻ gradient across the apical membrane drives the AE2 Cl⁻/HCO₃⁻ exchanger, resulting in net HCO₃⁻ secretion. This pathway can also be activated directly by biliary ATP secreted from upstream hepatocytes. Alternatively, inositol 1,4,5-trisphosphate (InsP3) formed from the stimulation of the M3 muscarinic receptor can stimulate secretion, although there is some evidence that this may act through Ca²⁺ released from ITPR1 and ITPR2 rather than ITPR3. Small cholangiocytes lack SRs and CFTRs, but have the same apical calcium signaling machinery to link to HCO₃⁻ secretion that is found in large cholangiocytes. Figure modified in part from References [9,30].