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.Corresponding author: Prof. Dr. Peter Hegyi, Doctor of the Hungarian Academy of Sciences, First Department of Medicine, University of Szeged, Koranyi fsr. 8-10, SZEGED, H6720, Hungary, TEL: +3662545200, FAX: +3662545185, MOBILE: +36703751031, hegyi.peter@med.u-szeged.hu. Conflict of interest statement: the authors have no conflict of interest to declare HHS Public Access I. Basics of CFTR a. Biosynthesis and degradationThe cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cyclic AMP (cAMP)-regulated chloride (Cl − )/bicarbonate (HCO 3 − ) channel, expressed in the apical plasma membrane (PM) of secretory epithelia in the airways, pancreas, intestine, reproductive organs and exocrine glands [1]. CFTR consists of two homologous halves, each containing a hexa-helical membrane spanning domain (MSD1 and MSD2) and a nucleotide binding domain (NBD1 and NBD2) (Figure 1). The two halves are connected by the R domain [2]. The NBDs contain conserved ATP-binding sequences: Walker A and B motifs, classifying CFTR as a member of the ATP-binding cassette (ABC) transporter family. Structural, biochemical and functional evidence suggest that the two NBD domains interact and the ATP-binding site of one NBD is complemented by the ABC signature motif of the other [2].While NBD1 folds largely co-translationally, the native fold of NBD2 as well as CFTR are attained post-translationally [3]. Assembly of MSD1, NBD1, R domain and MSD2 is necessary and sufficient to form the minimal folding unit of CFTR [4]. These and other observations support the cooperative domain folding model and ensure the dynamic conformational coupling between the cytosolic NBDs and the pore-forming MSDs in the native molecule and provide a structural explanation for the cooperative domain unfolding, caused by cystic fibrosis (CF) mutations [4].Despite interactions with several cytosolic and endoplasmic reticulum (ER) chapero...