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Biology 202
2004 First Web Paper
On Serendip

Ion Channels and Cystic Fibrosis

Kimberley Knudson

Ion channels are a crucial part to all cells. They are responsible for allowing ions in and out of the cell, which permit such things as muscle contraction to occur. But in these gated structures are there ever any malfunctions? If so, what is it that causes these problems in the channels and how are they manifested? It was through the disease cystic fibrosis that I attempted to answer these questions.

Cystic fibrosis is a genetically inherited disease in which chloride transport is the root cause of its symptoms. The easiest detectible symptom, and least detrimental, of cystic fibrosis (CF) is excessively salty sweat, chloride being one component of salt (NaCl). (1) Other more harmful manifestations of the disease are abnormal heart rhythms and thick mucus, which amasses in the lungs and intestines. The mucus cannot drain normally due to its thick viscosity and therefore becomes a breeding site for bacteria. People with CF generally acquire respiratory infections as well as other breathing difficulties. Complications involving lung function is the primary cause of death among CF patients. Additional symptoms include enlarged and rounded digits, abdominal discomfort and poor weight gain. (2)

Treatment of CF generally includes ingestion of digestive enzymes to reduce the abdominal problems, taking antibiotics to prevent lung infections, and thinning the mucus in the respiratory system for more efficient drainage. These treatments have transformed the prognosis of patients from certain death during childhood to an average life span of 30 years. (2) However, these treatments only reduce the symptoms and do not eliminate the cause. The reason these treatments are not able to eradicate the disease from a patient is the nature of what causes CF.

The disease is caused by an alteration in a single gene on chromosome 7. (3) This gene is responsible for producing a protein that regulates transmembrane conductance. Upon discovery of the gene and the protein it is responsible for producing, researchers named the protein cystic fibrosis transmembrane conductance regulator. In CF patients, this gene lacks 3 nucleotides that are in control of producing the amino-acid phenylalanine. Therefore, the defective cystic fibrosis transmembrane conductive regulator (CFTR) protein cannot manufacture phenylalanine. Every time CFTR is made, the defect is detected in the endoplasmic reticulum, (which is responsible for protein synthesis and insertion of proteins into the cellular membrane) and is marked for degradation, never making it to the cell membrane. This type of CF is most common. However, other forms of the disease manifest themselves in slightly different ways. (3)

Some CF patients are able to produce CFTR that is inserted into the cell membrane. However, the protein still malfunctions due to disruptions in the function of nucleotide binding sites. One such mutation in CFTR alters the amount of time the channel stays open, making it so that the protein closes at a faster rate than that of normal CFTR. (4)

In normal CFTR, triphosphates are required for proper function. Two nucleotide binding folds are present in the ion channel, each of which has unique functional traits. Nucleotide binding fold (NFB) 1 controls opening the ion channel and it is responsible for when the ion channel is closed. NBF 2 is also involved with when the channel opens but not when it closes. Adenosine triphosphate must bind to CFTR in order for ion gating to occur, but CFTR has many more binding sites for adenosine triphosphate (ATP) than is necessary for the protein to function correctly. This observation would imply that ATP is important for the extra negative charge that prepares the protein for ion gating. (5)

Much is unknown about the nature of CFTR dysfunction and relatedness to lung infections in CF patients. The molecular mechanisms are still being studied but many hypotheses have come forth over the years. None of them fully explain the means of viscous mucus production and bacterial propagation however. Clearly, the thick nature of the mucus is due to dehydration, if the secretions had more water in them they would be of a more normal consistency. However, studies have not shown differences in chloride concentrations in mucus located in the epithelial airways between people with CF and those that do not. Thus salt concentrations may not be the cause of dehydration in the fluid. The dysfunction in CFTR may be its inability to clear fluid from the surface of the lungs. (6) Again, the mechanism is still unknown making any hypothesis a speculation.

Even though the exact molecular cause for CFTR disruption and effect of poor chloride ion regulation in the epithelial cells are not known, research is being done on ways to cure CF. One such approach is looking at the regulatory domain within the CFTR protein and its interactions with NFB 1. Researchers are hoping to find a way to keep the ion channel open longer in order to allow more time for ion exchange. (6) This research would only benefit those with the mutant type that allowed CFTR to actually make it to the cell membrane. The vast majority of CF patients would not gain from this research because of the degradation of CFTR making it impossible for the protein to reach the cell membrane. Research for this type involves altering viruses to include the normal gene that produces functioning CFTR protein and infecting those with CF with this virus. This research is slow however because patients can build up immunity to the virus, and because the patient must be infected many times this proves a great hindrance in progress. (2)

In answer to the questions posed at the beginning, yes ion channels can malfunction. Malfunctions can even have a genetic cause. Ion channels can malfunction by improper formation making it impossible for it to get to the membrane surface. (2) They can also have gate problems, making it so that the channel is not open for the normally prescribed amount of time. (6) In the case of CF, these problems caused a build up of fluid in the lungs and intestines resulting in chronic infections leading to death. (1)

During the course of writing this paper a connected but different question arose. Since CF is a genetic disease what are the ethics behind two people reproducing who both knowingly have the recessive trait? (7) There is a one in four chance that their child could have CF with the only outcome being certain death by the age of 30 and a life of physical pain. Is it wrong for two people to become parents when they know that there is a strong possibility that their child could suffer most of his or her life?


1)Symptoms of cystic fibrosis, for general questions about CF

2)Welsh, M. (1995, December). Cystic Fibrosis. Scientific American, 52-59.

3)Cystic fibrosis gene

4)New Insights Into Cystic Fibrosis Ion Channel

5)Molecular Structure and Physiological Function of Chloride Channels

6)Pier, G. (2002). CFTR mutations and host susceptibility to Pseudomonas aeruginosa lung infection. Current Opinion in Microbiology, Vol. 5, Issue 1, 81-86.

7)Andre, J. (2000). On being genetically "irresponsible." Kennedy Institute of Ethics Journal, Vol. 10 No. 2, 129-146.

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