Figure 2.

Main mechanisms involved in biliary HCO⁻₃ secretion in cholangiocytes. Lower left: illustrates that the hormone secretin induces trafficking of vesicles with the chloride channel CFTR, the anion exchanger AE2/SLC4A2, and the water channel AQP1. Vesicle exocytosis at the apical membrane allows for bicarbonate-rich hydrocholeresis. Lower right: cholinergic stimulation of basolateral M3 muscarinic receptors increases InsP3 and leads to Ca²⁺ release. Activation of the apical Ca²⁺-dependent Cl⁻ channel TMEM16A results in efflux of Cl⁻ which is then exchanged with HCO⁻₃ via AE2. Moreover, CFTR activation that follows secretin stimulation may induce apical release of ATP with further stimulation of apical P2Y receptors, increases in InsP3 and Ca²⁺, activation of apical Ca²⁺-dependent Cl⁻ channel TMEM16A, Cl⁻ efflux and final AE2-mediated Cl⁻/HCO⁻₃ exchanger for apical HCO⁻₃ secretion. Upper right: release of ATP that follows PKC-dependent exocytosis of ATP-enriched intracellular vesicles upon increases in cell volume. Further stimulation of apical P2Y receptors may end up with apical HCO⁻₃ secretion as described for the CFTR-dependent release of ATP.