The membrane of various cells throughout the body hold CFTR protein channels, which control the transport of ions in and out of the cells to sustain pH homeostasis, electrically charged chloride ions (salt) levels, and fluid levels within epithelial tissues. Akabas (2000) describes the CFTR as an ATP-binding cassette (ABC) membrane transporter gene. There are 1480 amino acids producing two halves connected by the cytoplasmic regulatory domain (R-domain). The two halves create channels that allow negatively charged chloride ions to travel out of the cell (Thomson and Harris, 2008).
As demonstrated in the above diagram, the channel extends from extracellular area through the cell membrane and narrows at the charge selective filter as it enters the cytoplasm within the cell, finishing after the attachment of the anion binding site (Hwang & Sheppard, 2009). Figure 3 demonstrates how the CFTR is assembled of five domains; two membrane-spanning domains (MSDs) are purple and green, two nucleotide-binding domains (NBDs) blue and green, and a unique regulatory domain (RD) red (Hwang & Sheppard, 2009).
Recent research by Hwang and Sheppard (2009) explains that MSDs form the low conductance anion selective pore. Selecting for only chloride ions to exit the cell. Gadsby and Nairn (1999) explain that the R-domain is the site for phosphorylation. This is the prerequisite for opening the chloride channels and is the activity determining the level of CFTR activation. It controls the chloride ion transport. The more phosphorylation the higher the probability of the channel opening according to Akabas (2000). The multiple locations for phosphorylation include c-AMP dependent protein kinases (PKA), and protein kinase C (PKC) (Gadsby & Narin, 1999). Following this Hwang and Sheppard (2009) say ATP binding and hydrolysis occurs at the NBDs, they have two binding sites, the interaction of ATP with binding sites regulates the flow of anions through the chloride ion channel. During one open-close cycle, ATP binds to the first site NBD1 and is hydrolyzed, this release of energy opens the MSDs pore, allowing active transport of the chloride ion through the cell membrane. Then a second ATP is bound NBD2 and hydrolyzed charging the closure of the channel (Gadsby & Nairn, 1999). Lastly, at the R-domain, the phosphatases protein returns the channel to its inactive state (Sheppard & Welsh, 1999).
The Cystic Fibrosis Foundation [CFF] (2010) states the 1400 CFTR gene mutations are classified into 6 groups
Class 1: The mutation occurring in around 10% of patients interferes with the protein synthesis, there is a premature stop codon so translation of mRNA ends early resulting in no protein present in the cell membrane. (Pettit, 2013)
Class 2: Complications occur in maturing of the protein, primarily resulting in trafficking defects. CFTR protein does not fold correctly or transport to the cell membrane.
Class 3: These are mutations occurring in a small percentage of...