Cell Processes: Traffic across epithelial cells: chloride secretion Flashcards
What is a NaK2Cl symporter
Transporter that uses the energy of the Na gradient to actively accumulate chloride above its electrochemical gradient (in chloride secretion)
How does Cl leave cell in chloride secretion?
Cl leaves the cell by passive diffusion through an ion channel (exit step = secretion) it is selective for Cl- and gated (regulated)
Why and how does Na and K leave cell in chloride secretion
Na exits via the basolateral Na-pump and K + via channel (K leaving makes cell more negative, so Cl- will want to leave negative environment)
What does the transport of Cl across the epithlium do?
induces paracellular Na and water fluxes (creates negative environment which attracts positive ions)
What is the rate limiting step of chloride secretion
Cystic Fibrosis Transmembrane conductance Regulator (CFTR) (channel shut = no Cl- movement, no isotonic secretion)
What causes secretory diarrhoea?
Caused by excessive stimulation of the secretory cells in the crypts of the small intestine and colon
Cells become over stimulated pump out a lot of Cl- so a lot of Na and water (exceeding capacity to reabsorb fluid in gut)
One possible cause of excessive stimulation of the secretory cells. These molecules are produced by tumours and inflammation.
abnormally high concentrations of endogenous secretagogues
What are the crypts
Location of secretory cells in the small intestine and colon
A cause of excessive stimulation of the secretory cells due contaminated water
secretion of enterotoxins from bacteria such as Vibrio cholerae
What are enterotoxins
toxins that irreversibly activate adenylyl cyclase causing a maximal stimulation of CFTR lead to a secretion that overwhelms the absorptive capacity of the colon
What does oral therapy treat?
secretory diarrhoea caused by cholera
5 step cholera toxin mechanism
cholera toxin irreversibly acts on adenylyl cyclase -> excess cAMP produced -> protein kinase A phosphorylates R region of CFTR -> ATP binds to nucleotide binding domain -> CFTR channel stays open
What are villus cells involved in?
Absorption
What is cystic fibrosis
A genetic disorder affecting children and young adults, usually ending in death from respiratory issues.
How is cystic fibrosis inherited
It is inherited in an autosomal recessive fashion (Heterozygotes have no symptoms but are carriers)
Likelihood of a child from two carriers getting cystic fibrosis
1/4
Proportion of Northern European newborns affected by CF
1 in 2500
Proportion of Northern Europeans who are carriers of CF
1 in 25
6 organs commonly affected by CF
Airways, liver, pancreas, small intestine, reproductive tract, skin
4 treatments to manage CF and increase survival time
chest percussion, antibiotics, enzyme replacement, attention to nutrition
Most common way cystic fibrosis kills people
respiratory failure
Median survival of patients with CF
38 years
What does CFTR stand for
Cystic fibrosis transmembrane conductance regulator
What is CFTR
Cl channel regulated by protein kinase A dependent phosphorylation of the R domain and binding of ATP to the NBD (nucleotide-binding domain)
What causes R domain to leave CFTR pore
Binding of ATP to cause R domain to leave pore
The absence of functional CFTR receptors in the lungs creates a
dry lung surface
CFTR lung pathology (7)
CFTR gene defect -> defective ion transport -> airway surface liquid depletion -> defective mucociliary clearance -> mucus obstruction, infection, inflammation
What does a normal lung epithelial cell do in Cl secretion
it has a balance between secretion and absorption keeping the lung surface moist and prevents excessive fluid build up
What does a lung epithelial cell do in CF
the defective Cl- channel prevents isotonic fluid secretion and enhances Na+ absorption to give a dry lung surface
Two stages of sweat formation
Primary isotonic secretion of fluid (by acinar cells), secondary reabsorption of NaCl to produce a hypotonic solution (by duct cells)
What does failure to reabsorb NaCl in ducts of sweat glands do?
produce salty sweat in CF patients
Neurotransmitters that stimulate sweat production
ACh (Acetylcholine), NA (Noradrenaline)
Parasympathetic stimulation of sweat production uses…
ACh
Sympathetic stimulation of sweat production uses…
NA
What is CLCA
Chloride channel accessory, controlled by calcium - in Acini, controls secretion of Cl-
What is ACh
Neurotransmitter that activates CLCA
What is NA
Neurotransmitter that activates CFTR
What is ENaC
Epithelial sodium channel, responsible for reabsorbing sodium out of the sweat.
What special about CFTR
It is the only chloride channel responsible for reabsorbing chloride from sweat
in sweat formation, why do Cl want to enter cell down electrochemical gradient
duct cells the membrane potential is depolarised
Where does Cl- accumulate in CF patients
Cl- accumulates in the duct lumen producing salty sweat
