CFTR protein

The cystic fibrosis transmembrane conductance regulator (CFTR) protein helps to maintain the balance of salt
and water on many surfaces in the body, such as the surface of the lung. When the protein is not working
correctly, chloride -- a component of salt -- becomes trapped in cells. Without the proper movement of chloride,
water cannot hydrate the cellular surface. This leads the mucus covering the cells to become thick and sticky,
causing many of the symptoms associated with cystic fibrosis.

The protein sequence of the CFTR is composed of 1480 amino acids.

It consists of two repeated motifs each composed of a hydrophilic membrane-spanning domain (MSD)
containing six helices and an important hydrophilic region for binding with ATP (NBF or Nucleotide Binding
fold). These two motifs are linked by a cytoplasmic (R domain) encoded by exon 13, containing a number of
charged residues and the majority of the phosphorylation sites (probable substrates of protein kinases A and/or
C).
The bacterium Vibrio
cholera has co-opted
this channel with
devastating results.

There are an estimated

3 – 5 million cases of
cholera, a disease
caused by the
bacterium Vibrio
cholera, each year. It
is passed on through
drinking water that
has been contaminated
with feces from
someone infected with
the bacteria. Cholera
causes vomiting and
diarrhea, leading to
severe dehydration.

What are ion

channels?

Ion channels are membrane proteins that, when open, allow ions (charged atoms) to pass through them into or
out of the cell. Several different things can open ion channels: some ion channels open because of changes in
voltage, and others open because of a chemical (ligand) binding to them. In cholera, dehydration occurs because
of chloride ion channels.

A type of chloride ion channel called the cystic fibrosis transmembrane conductance regulator (CFTR) normally
allows chloride ions to flow out of cells. In small intestine cells the CFTR channel is used to adjust water levels:
a higher concentration of chloride ions outside the cell will cause water to leave by osmosis. Cholera disrupts
this process.
How does cholera affect ion channels?

The cholera bacteria produce a toxin that is made of six protein subunits. The cholera toxin binds to receptors
on cells in the wall of the small intestine and activates cyclic AMP (cyclic adenosine monophosphate, a
messenger molecule), increasing the number of cyclic AMP molecules in the cell.

As CFTR channels are activated by cyclic AMP, the increased concentration of cyclic AMP causes the CFTR
channels to open and stay open. This means that chloride ions (Cl–) move out of the cell into the lumen (the
inside of the small intestine tube). Sodium ions (Na+) are attracted to the negative chloride ions, so they also
leave the cell.

With more ions in the lumen, the lumen has a lower water potential. This makes water leave the cells lining the
lumen by osmosis, down the concentration gradient. The cells lose a lot of water, which causes severe
dehydration, and the increased water in the small intestine causes watery diarrhea and vomiting.