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The cystic fibrosis trans membrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl− channel. It is located predominantly in the apical membrane of epithelia where it mediates trans epithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function.
The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.
The severity and type of clinical manifestations are variable in patients with cystic fibrosis (CF).
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The respiratory syndromes in these patients consist of lung infections associated with disseminated bronchiectasis (DB), asthma, and chronic obstructive pulmonary disease. To investigate the possible involvement of the cystic fibrosis trans membrane conductance regulator (CFTR) gene in chronic pulmonary disease in adults, we studied 32 DB patients with a clinically isolated respiratory syndrome. Careful analysis of all the CFTR gene exons and their flanking regions revealed a significantly increased frequency of CFTR gene mutations in these patients. Thirteen CFTR gene mutations were identified in sixteen different alleles.
Six of these mutations, which have previously been reported as CF defects, were found on nine alleles. A further four, two of which had not previously been described, are potentially disease-causing mutations. We also identified three rare substitutions, which could be involved in mild CFTR gene disease. Four patients were compound heterozygotes, one carried two CFTR gene mutations (possibly allelic) and six were heterozygous for a mutation. These results indicate that CFTR gene mutations may play a role in bronchiectasis lung disease, possibly in a multifactorial context. These findings have implications for genetic counseling of DB patients and their families.
Diffusion through the cell membrane is divided into two subtypes called simple diffusion and facilitated diffusion.
In simple diffusion movement of ions and molecules happens without any use of carrier proteins in the membrane. In the other hand in facilitated diffusion we need carrier proteins that bind chemically to ions and molecules.
Osmosis is the passage of water from a more concentrated place to a less concentrated one through a semipermeable membrane by the application of pressure.
In primary active transport energy is derived directly from breakdown of ATP but in secondary active transport this energy is derived secondarily from energy that has been stored in the form of ionic concentration differences of secondary molecule or ionic substances between the two sides of a cell membrane.
There are two forms of secondary active transport which are co-transport and counter-transport.
CF is through loss of its function as a chloride ion transporter, caused by the misfolding of the protein. While researching, I noticed this became the principal focus due to its role as the primary cause of the CF phenotype and its predominance in the literature. CFTR, when mutated, leads to a well-defined and well-known set of symptoms unique from any other disease. CFTR is a highly researched protein and therefore has become well-understood. Although there has yet to be a cure discovered for this debilitating and often fatal genetic disease.
The exact mechanisms of CFTR folding, transport, and destruction are unknown. Through knowledge of these detailed mechanisms, I believe several drug targets could expose themselves, leading to a substantial increase in the standard of living for severely affected CF patients.
First, it is not well-understood how the folding of CFTR occurs or exactly how phosphorylation affects CFTR. The correct folding of CFTR is necessary for the protein to function as a transporter. Misfolded CFTR does not allow chloride to pass through, leading to an imbalance of water in mucus. It is known that the regulatory domain of CFTR is necessary for correct folding, via phosphorylation of its serine residues by PKA and PKC. But it has not been found how exactly PKA and PKC work together (or separately) to phosphorylate the correct amount and exact serine residues. I propose that further studies examine the roles of PKA and PKC in CFTR phosphorylation to determine if 1) phosphorylation by PKA and PKC reaches mutant CFTR protein, 2) PKA and PKC could be supplemented to increase phosphorylation of CFTR, and 3) if this increase in PKA and PKC leads to increased phosphorylation of mutant, not just wild type CFTR. If this is possible, it would result in increased functionality of mutant CFTR proteins in CF patients, leading to a decrease in the thickness and stickiness of their mucus.
Secondly, the transport of CFTR beginning from nascent polypeptide and ending in apical membrane localization is not well known. The transport of CFTR is critical if CFTR is to be of use. A perfect CFTR protein is unable to perform its job of ion transport across membranes if it never becomes localized to the membrane. I suggest that more research be done to clarify every step of CFTR transport. Perhaps insight into how CFTR is transported could eventually lead to the ability to effectively increase or direct transport of CFTR to appropriate locations within the body. Maybe some mutations in CF lead to decreased recognition by transporter proteins, leading to failure of appropriate transport. Or possibly, more effective transport of CFTR could lead to a decreased phenotype, because the greater amount of CFTR would offset the imbalanced chloride ion gradient.
Lastly, it is known that a defective CFTR protein, if recognized, will be ubiquinated and subsequently destroyed by the proteasome. But it is unknown by which mechanisms the mutant CFTR protein is recognized and where it is recognized. I recommend that more research be focused on the degradation of CFTR protein within cells. It should be determined when is CFTR degraded, during translation or transport or within the membrane. It should also be determined if mutant CFTR has the same lifetime as a wild type CFTR protein. Current research is focused on “rescue proteins” (such as vasoactive intestinal peptide) which save functional CFTR proteins. Maybe some CF patients do not have a mutation within the CFTR gene, but within the gene that codes for the degradation protein targeted for CFTR. Maybe a drug can be found which acts as an antagonist to this degradation protein, turning it off an allowing the CFTR to be transported successfully. Perhaps researchers could create a drug that resembles some sort of heat shock protein or other molecular chaperone to protect it from degradation as it is transported. The preservation of CFTR is essential, increased degradation would lead to a more severe phenotype and increased rates of fatality; therefore, it follows that increased preservation would lead to decreased symptoms.
Structure And Function Of The CFTR Chloride Channel. (2024, Feb 21). Retrieved from https://studymoose.com/structure-and-function-of-the-cftr-chloride-channel-essay
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