Fig. 1.

A. Cholangiocyte secretory functions. The most widely accepted model of ductal bile formation involves [1] secretin activation of the cAMP-PKA signaling pathway, which then leads to [2] activation of CFTR, causing extrusion of Cl⁻. This then stimulates the [3] Cl⁻/HCO₃⁻ exchanger which secretes HCO₃⁻ and creates an osmotic gradient that leads to the [4] passive movement of water across AQP1. More recently, an alternative hypothesis suggests that [5] activation of CFTR leads to the release of ATP, which then phosphorylates IP₃R on the endoplasmic reticulum. This causes the release of Cl⁻ via the [6] Ca²⁺-dependent Cl⁻ channel, which creates a gradient leading to [3] activation of the Cl⁻/HCO₃⁻ exchanger. Ca²⁺ is also transported via a [7] Ca²⁺- and cAMP-independent Cl⁻ channel. Finally, the apical membrane also contains [8] K⁺ channels (SK2 and IK-1) and a [9] Na⁺-HCO₃⁻ cotransporter (mice). On the basolateral domain, there are two types of K⁺ channels: [10] SK2 and [11] IK-1. There is also [12] a Na⁺/K⁻ ATPase, [13] a Na⁺/H⁺ exchanger (NHE1), [14] a Na⁺/K⁺/Cl⁻ cotransporter, [15] a Na⁺/HCO₃⁺ cotransporter (rats), [16] a Na⁺-dependent Cl⁻/HCO3⁻ exchanger (humans), and water channels, [17] AQP1 and [18] AQP4. Within the cell, [19] carbonic anhydrase allows for the production of HCO₃⁻. Abbreviations: ATP, adenosine triphosphate; AQP, aquaporin; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; IK-1, intermediate-conductance K+ channel; PKA, protein kinase A; NHE, Na⁺/H⁺ exchanger; SK2, small conductance K⁺ channel.

B. Cholangiocyte absorptive functions. Cholangiocytes have a number of transporters that allow the absorption of a variety of molecules [1]. Glucose is absorbed through SGLT1, Na⁺ is absorbed through [2] NHE2 and [3] NHE3, glutamate is absorbed through a glumate transporter, bile acids are absorbed through [5] ASBT and [6] iBAT and [7] water is absorbed through AQP1. On the basolateral membrane, [8] glucose is transported via GLUT1, bile is transported via [9] Ostα-Ostβ and [10] t-ASBT, water is transported via [11] AQP1 and [12] AQP4. Lastly, the basolateral membrane contains a [13] Na⁺/H⁺ exchanger (NHE3). Abbreviations: ASBT, apical sodium-dependent bile acid transporter; AQP, aquaporin; BA, bile acids; GLUT, glucose transporter; GT, glutamate transporter; iBAT, ileal bile acid transporter; NHE, Na⁺/H⁺ exchanger; OST, organic solute transporter alpha; SGLT, Na⁺-Glucose cotransporter.