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Abstract
The Cl−/HCO−3anion exchanger 2 (AE2) is known to be involved in intracellular pH (pHi) regulation and transepithelial acid-base transport. Early studies showed that AE2 gene expression is reduced in liver biopsies and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a disease characterized by chronic non-suppurative cholangitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. Microfluorimetric analysis of the Cl−/HCO−3 anion exchange (AE) in isolated cholangiocytes showed that the cAMP-stimulated AE activity is diminished in PBC compared to both healthy and diseased controls. More recently, it was found that miR-506 is upregulated in cholangiocytes of PBC patients and that AE2 may be a target of miR-506. Additional evidence for a pathogenic role of AE2 dysregulation in PBC was obtained with Ae2−/−a,b mice, which develop biochemical, histological, and immunologic alterations that resemble PBC (including development of serum AMA). Analysis of HCO−3 transport systems and pHi regulation in cholangiocytes from normal and Ae2−/−a,b mice confirmed that AE2 is the transporter responsible for the Cl−/HCO−3exchange in these cells. On the other hand, both Ae2+/+a,b and Ae2−/−a,b mouse cholangiocytes exhibited a Cl−-independent bicarbonate transport system, essentially a Na+-bicarbonate cotransport (NBC) system, which could contribute to pHi regulation in the absence of AE2.
Highlights
Intracellular pH regulation plays a critical role for most cellular processes and functions
A particular attention is paid to the anion exchanger 2 (AE2, Slc4A2), a pH regulatory protein that is highly activated upon increased pHi (Stewart et al, 2001)
AE2 is efficiently used by cholangiocytes to execute biliary HCO−3 secretion and its dysfunction is seemingly involved in the pathogenesis of primary biliary cirrhosis (PBC)
Summary
Intracellular pH (pHi) regulation plays a critical role for most cellular processes and functions. To minimize cytosolic pH disturbances, cells employ their intrinsic buffering capacity but have a variety of ion carriers at the plasma membrane that maintain the pHi within a narrow physiological range (Boron et al, 2009; Casey et al, 2010). These include channels, pumps, exchangers, and cotransporters, all of which orchestrate the input and output of acid/base ions H+and HCO−3. In order to maintain the overall HCO−3 -secretory function, cholangiocytes are provided with specific ion membrane carriers like acid loaders and acid extruders (Figure 1) which allow them to maintain ion gradients and pHi (Strazzabosco et al, 1991; Banales et al, 2006b; Tabibian et al, 2013)
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