Cystic Fibrosis Transmembrane Conductance Regulator Assays
Background of Cystic Fibrosis Transmembrane Conductance Regulator
The cystic fibrosis transmembrane conductance regulator (CFTR) is the only member of the ABC transporters family to act as a chloride channel. CFTR is a 1480 amino acid glycoprotein consisting of 7 domains. There are 2 transmembrane domains in the CFTR structure, each of which has a 6-span alpha-helix and is linked to a nucleotide-binding domain (NBD) in the cytoplasm.
Expression and Functions of Cystic Fibrosis Transmembrane Conductance Regulator
In humans, the expression of CFTR can be found in the epithelial cells of various organs, such as the lung, liver, pancreas, digestive tract, as well as female and male reproductive tracts. The protein allows chloride and thiocyanate ions to move from epithelial cells to airway surface fluid and mucus. In sweat glands, mutated CFTR results in a reduced transport of sodium chloride and sodium thiocyanate in the reabsorptive duct. This phenomenon could serve as the basis for a clinically important cystic fibrosis sweat test for diagnostic genetic screening.
Fig.1 Cartoon illustrating how ATP binding and subsequent hydrolysis could lead to channel opening and flux of chloride ions. (Meng, 2017)
Diseases Associated with Cystic Fibrosis Transmembrane Conductance Regulator
CFTR conducts chloride ions across epithelial cell membranes, and mutations in the CFTR gene may affect chloride channel function and lead to cystic fibrosis. Subsequent complications may also include thickening of mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency leading to malnutrition and diabetes. There are already drugs developed targeting CFTR for the treatment of cystic fibrosis.
Published Data
| Paper Title | Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation |
| Journal | The Journal of clinical investigation |
| Published | 2020 |
| Abstract | An inflammatory response followed by terminal respiratory failure is a cardinal feature of cystic fibrosis (CF) lung disease. Mutations in CF of cystic fibrosis transmembrane conductance regulator (CFTR) are key players in the immune response and serve as major determinants of CF inflammation. Furthermore, loss of CFTR in platelets leads to severe acute lung inflammation and platelet activation. Inhibition of transient receptor potential cation channel 6 (TRPC6) was found to inhibit platelet activation and calcium flux, and relieve lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. The present paper demonstrates that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation and ultimately leads to impaired lung inflammation and bacterial clearance in CF. Therefore, platelets and TRPC6 have emerged as new targets for the treatment of CF lung disease. |
| Result |
Emerging data implicate hematopoietic cell dysfunction in spreading CF inflammation. Major defects in immune cells in CF may lead to chronic and acute (neutrophil) inflammation as well as neutrophil extracellular trap (NET) formation. The major defect in CF platelets is an upstream trigger of neutrophil inflammation and NET formation in CF lung disease. These data allow us to redefine a new role for CFTR in maintaining platelet homeostasis. In the setting of CFTR dysfunction, CF platelets are activated during acute inflammation and lead to neutrophil lung injury. CFTR function on platelets can be modestly restored by directly targeting TRPC6 in platelets.
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Fig.2 Graphical abstract indicating key events in platelet-induced neutrophilic inflammation in CF. (Ortiz-Muñoz, et al., 2020)
References
- Meng, X.; et al. The cystic fibrosis transmembrane conductance regulator (CFTR) and its stability. Cellular and Molecular Life Sciences. 2017, 74(1): 23-38.
- Ortiz-Muñoz, G.; et al. Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation. The Journal of clinical investigation. 2020, 130(4): 2041-2053.
