section 12.3
Digestion and Absorption of Major Food Substances
2 2 1
Protein
kinase A
cAMP
A deny ly I
" cyclase
Stimulatory
G Protein
V. ( holer;
I .u men
iXtO
C ho era Toxin
n Ik
(»Ml
Receptor
Apical Membrane
Il N
ADP
( OOH
AI P
/.ona
( Veuillons
Membrane
Ü O lg l
li.tsol.llei.il
\l I*
\DP Kibose
Nucleus
K+
K+
Na*
Na+
K+
FIGURE 12-15
Mechanism of action of cholera toxin. The steps consist of cholera toxin (CT) binding to GMi receptors anchored by its
ceramide moiety; internalization of CT in endosomes; the release of A1-subunit of CT from the trans-Golgi network and
endoplasmic reticulum (ER); ADP ribosylation of the a-subunit of stimulatory G-protein by Al; activation of adenylyl
cyclase and production of cAMP; activation of protein kinase A; phosphorylation of the regulatory (R) subunit of CFTR;
and finally opening of the chloride channel.
Vibrio cholerae
also produces a zona occludens toxin (ZOT) which
increases the ionic permeability of the zona occludens.
3. Regulation of the channel, and
4. Conduction.
The most common mutation causing CF is a 3-
base pair deletion resulting in loss of a phenylalanine
(F) residue at position 508. This deletion (AF508), is
found in about 70% of CF patients worldwide and
is associated with severe disease. The AF508 muta-
tion belongs to the category
2
defect and involves the
folding of the first nucleotide binding domain. The
phenylalanine-deficient CFTR protein gets trapped in the
endoplasmic reticulum and is degraded. The G1349D
mutation occurs in the second nucleotide binding do-
main. In general, genotype-phenotype correlations with
clinical manifestations are difficult to interpret in CF
patients.
As discussed earlier, the Cl- transport defect occurs in
association with hyperabsorption Na+ ions. The mecha-
nism of regulatory interaction between CFTR and the Na+
channel is not clear. Flowever, two possible mechanisms
may play a role:
1. A direct protein-protein interaction or,
2. A physical coupling of channel proteins mediated by
the cytoskeleton.
It is thought that CFTR participates in the regulation of
Cl“ transport within intracellular membranes as being a
regulator of other ion conductances.
The diagnosis of CF includes the clinical features of
chronic obstructive lung disease, persistent pulmonary in-
fection, meconium ileus, and pancreatic insufficiency with
failure-to-thrive syndrome. Family history is also very
helpful. The diagnosis can be confirmed by a positive
sweat chloride test in which a concentration of chloride
ions is greater than 60 meq/1. The genotype is confirmed
by DNA analysis, and carrier detection in CF families
is useful in genetic counseling. Newborn screening, al-
though not universally accepted, consists of quantitation
