Cystic Fibrosis ABCC7CFTR

Cystic fibrosis, caused by mutations in ABCC7 (CFTR) (Tab. 3.2) is one of the most frequent inherited diseases in Caucasian populations with a prevalence of 1:900 to 1:2500, whereas African and Asian individuals are affected to a much lesser extent. Interestingly, a three base pair deletion (AF508) accounts for 70-80% of the mutated alleles in northern European populations. The total number now comprises more than 1000 CFTR mutations (http://www.genet.sickkids.on.ca/cftr/). The spectrum of the disease severity is dependent on the residual function of ABCC7 [164, 165]. Patients with two affected alleles develop a severe disease with a disturbed exocrine function ofthe pancreas leading to nutritional deficiencies, bacterial lung infections, and a blockade of the vas deferens causing male infertility. In

Nherf Dimer

Fig. 3.4 Schematic diagram summarizing ABCC7 (CFTR) interactions in the plasma membrane. CFTR interacts with various proteins in the plasma membrane including syntaxin 1a, CAL (CFTR-associated ligand), and EBP50/NHERF [1 70-175]. Syntaxin 1a contains coiled-coil protein motifs which bind the N-terminal part of CFTR. Syntaxin 1a controls the vesicular trafficking of CFTR through the Golgi to the plasma membrane and thereby inhibits its channel function. CFTR also contains a PSD-95/Disc-large/ZO-1 (PDZ)-inter-acting motif at its C-terminus, which binds the PDZ-proteins CAL and EBP50/NHERF (ezrin, radixin, and moesin) binding phospho-protein of 50 kDa/Na+/H+ exchanger regula tory factor). CAL has one PDZ domain and two coiled-coil motifs, which organize CFTR into a cluster in the apical membrane. EBP50/NHERF binds to CFTR through its PDZ1 domain and thereby links the protein to the cytoskeleton via ezrin. Ezrin serves as a PKA-anchoring protein and facilitates cAMP-dependent phosphorylation of the CFTR regulatory domain and channel activity. In addition to these direct protein-protein interactions, CFTR indirectly regulates several ion channels such as ROMK2, ENaC, CaCC, and ORCC. CaCC and ORCC are activated by Ca2+-dependent purinergic receptors (P2Y2), which are in turn modulated by CFTR-dependent ATP release.

contrast, patients with one partially functional allele retain residuary pancreatic function and have a milder disease phenotype [166].

Before ABCC7/CFTR was identified, it was known in the 1980s that the apical membrane of different epithelia displays a Cl- conductance, which could be activated by cAMP and which was defective in cystic fibrosis. With the identification of the ABCC7/CFTR gene in 1989 [167] and an impressing multitude of publications in the following years, it became more and more evident that ABC transporters are not exclusively ATP-driven pumps, but moreover can exhibit a regulatory and/or channel function. As depicted in Fig. 3.4, ABCC7/CFTR can act as a cAMP-regulated chloride channel as well as a regulator of outwardly rectifying chloride channels (ORCC) [88, 168]. In both cases targeting to the apical membrane of epithelial cells and activation of the regulatory (R) domain by PKA are a prerequisite for proper ABCC7 function.

It is now widely recognized that ABCC7 interacts with various proteins in the plasma membrane [169]. Thus, the N-terminus of CFTR binds the coiled-coil protein syntaxin 1a and the C-terminal region of CFTR binds to PDZ domain proteins, a family of proteins containing a 80-90 amino acid motif that binds the C-terminus of a variety of ion channels and receptors [170]. At least three PDZ domain-containing proteins, NHE-RF or EBP50, CAP70, and CAL, bind to the CFTR C-terminus (Fig. 3.4) [170-174]. Because EBP50 associates with Ezrin, which itself binds the regulatory subunit of PKA and has a binding site for F-actin [175], it is likely that EBP50 anchors CFTR to the actin cytoskeleton at a site where it can be targeted by PKA. CAP70, a subapical protein, is able to bind two ABCC7 molecules simultaneously via PDZ3 and PDZ4 [173] and thus can mediate cross-linking of CFTR dimers and thereby enhance either direct or indirect (ORCC) chloride channel activity. Taken together, the N-terminus of ABCC7 is required for binding of syntaxin 1a and other components of the SNARE-dependent vesicular trafficking machinery, whereas the C-terminus of CFTR is necessary for cytoskele-tal fixation via EBP50/Ezrin proteins. In addition, multimerization of CFTR molecules could be potentially achieved by CAP70-dependent linkage.

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