Abstract
Cystic fibrosis (CF) is the most common genetic disorder that causes a significant damage in secretory epithelial cells due to the defective ion flux across the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Pancreas is one of the organs most frequently damaged by the disease leading to pancreatic insufficiency, abdominal pain and an increased risk of acute pancreatitis in CF patients causing a significant decrease in the quality of life. CFTR plays a central role in the pancreatic ductal secretory functions by carrying Cl- and HCO3- ions across the apical membrane. Therefore pathophysiological studies in CF mostly focused on the effects of impaired ion secretion by pancreatic ductal epithelial cells leading to exocrine pancreatic damage. However, several studies indicated that CFTR has a central role in the regulation of intracellular signaling processes and is now more widely considered as a signaling hub in epithelial cells. In contrast, elevated intracellular Ca2+ level was observed in the lack of functional CFTR in different cell types including airway epithelial cells. In addition, impaired CFTR expression has been correlated with damaged mitochondrial function in epithelial cells. These alterations of intracellular signaling in CF are not well characterized in the exocrine pancreas yet. Therefore in this review we would like to summarize the complex role of CFTR in the exocrine pancreas with a special focus on the intracellular signaling and mitochondrial function.
Highlights
In nonstimulated cells the unphosphorylated R domain binds to NBD1 preventing the interaction of NBD1 with NBD2 and ATP hydrolysis, which is mandatory for the opening of the channel
Supporting this idea in 2013 Namkung et al (2010) have reported the regulation of CFTR by AC1. They suggested that CFTR in primary cultures of human bronchial epithelial cells is regulated by intracellular Ca2+ that activates AC1 and the downstream cAMP/protein kinase A (PKA) signaling
This study showed that CFTR and transient receptor potential canonical 6 (TRPC6) are functionally coupled within a molecular complex in airway epithelial cells, which is lost in Cystic fibrosis (CF) leading to abnormally increased TRPC6-dependent Ca2+ influx (Antigny et al, 2011b)
Summary
AC isoforms are localized in different nanodomains of the plasma membrane. The Ca2+ regulated AC1, AC5, AC6, and AC8 are FIGURE 2 | Regulation of CFTR by the intracellular Ca2+. Targeted into lipid rafts in the plasma membrane, whereas the Ca2+ independent AC2 and AC7 are excluded from these rafts (Delint-Ramirez et al, 2011; Ahuja et al, 2014) This integrated subcellular localization could potentially promote the regulation of AC activity and intracellular cAMP levels through Ca2+. Supporting this idea in 2013 Namkung et al (2010) have reported the regulation of CFTR by AC1 They suggested that CFTR in primary cultures of human bronchial epithelial cells is regulated by intracellular Ca2+ that activates AC1 and the downstream cAMP/PKA signaling. They have found the colocalization of the two in the apical membrane of the cells suggesting that. These together lead to increased ER Ca2+ concentration, which might further impair the folding of CFTR since decreasing and maintaining low ER Ca2+ level promotes the correction of defective F508delCFTR (Norez et al, 2006)
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