CFTR: A New Horizon in the Pathomechanism and Treatment of Pancreatitis

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis, and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking, or bile acids, strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis.

Keywords: CFTR; Cystic fibrosis; Epithelial transport; Pancreas; Pancreatitis.

Figure 1. Schematic structure of CFTR

The CFTR Cl⁻ channel consists of two homologous halves, each containing a hexa-helical membrane spanning domain (MSD1 and MSD2) and a nucleotide binding domain (NBD1 and NBD2). The two halves are connected by the R domain.

Figure 2. Biosynthesis and maturation of CFTR

Only a fraction of newly synthesized and cotranslationally core-glycosylated channels undergoes conformational maturation in the endoplasmic reticulum (ER). The natively folded channel is then transferred by vesicular transport to the cis/medial-Golgi, where CFTR is complex-glycosylated before being delivered to the plasma membrane (PM). Unfolded CFTR, similar to other damaged proteins, is rapidly removed from the PM upon ubiquitination by the PM quality control (QC) system. CFTR ubiquitination accelerates internalization, impedes recycling and facilitates preferential sorting towards lysosomal degradation. The six major classes of mutations are highlighted in yellow and treatment options in green.

Figure 3. Mechanism of transepithelial fluid secretion in the gastrointestinal tract

In epithelial tissues CFTR is usually expressed on the apical PM mediating the rate-limiting step for anion (chloride and bicarbonate) secretion, which ultimately controls transepithelial fluid secretion and hence hydration of the luminal surface. During electrogenic Cl⁻ secretion, Cl⁻ is transported into the cells via the basolateral membrane by the Na⁺/K⁺/2Cl⁻ cotransporter that is followed by the Cl⁻ transport through the apical membrane via the CFTR channel.

Figure 4. Regulation of CFTR gating

CFTR gating is regulated by the R domain which contains multiple PKA and PKC phosphorylation sites and which physically interacts with NBD1. CFTR uses the energy of ATP binding and hydrolysis to drive ligand-induced conformational changes in the protein that lead to the regulated opening and closing (gating) of the channel ‘pore’.

Figure 5. CFTR dysfunction in pancreatitis

Under physiological conditions (left) CFTR (red) is expressed on the luminal membrane of small inter/intralobular pancreatic ducts with the SLC26A6 Cl⁻/HCO₃⁻ exchanger (yellow). This expression and the close connection of the two proteins are required for the maintenance of the alkaline luminal pH. During acute pancreatitis (middle) the function of CFTR is inhibited and its expression is decreased leading to impaired bicarbonate and fluid secretion and consequently decreased luminal pH. The washout of the activated digestive enzymes is insufficient. Overall, these changes together will increase the severity of acute pancreatitis. In chronic or autoimmune pancreatitis (right), CFTR expression is markedly decreased leading to the described consequences. The more viscous, protein-rich ductal fluid promotes the formation of intraluminal protein plugs. The intraductal obstruction will result in pancreatic atrophy and exocrine pancreatic insufficiency.