CFTR and salt secretion Flashcards
Features of cystic fibrosis
Most common lethal genetic disease in Caucasians
exocrine pancreatic insufficiency- struggle to breakdown food
increased sweat
male infertility
airway disease
Which cells secrete NaCl?
exocrine gland acini sweat gland coil small intestine upper airway cells choroid plexus
What was the first model for looking at chloride secretion
Shark rectal gland
What blockers did they add to shark rectal gland, what was the conclusion?
Ouabain
barium
furosemide
Na/K ATPase, K channel and NA/K/2cl co transporter are all absolutely critical for chloride secretion, blocking each one= 0 secretion
Na/K ATPase maintains low IC Na, the K channel sets up the negative membrane potential- both are required for na uptake into the cell and thus chloride secretion
the co transporter brings cl into the cell- all 3 are required for CHLORIDE SECRETION
What ionic species did they all target in the shark rectal gland experiment, what happened?
They removed sodium and then potassium from the extracellular fluid
resulted in no secretion
How did they know that there was an active component in the uptake of chloride into the cell?
Rearranged the nernst potential for chloride to work out the IC Cl conc = 17mM
The actual conc is 70mM, the equation only works when movement is massive
Na/K ATPase is the active component
How does furosemide affect the chloride electrochemical equilibrium?
Furosemide brings Ecl to its equilibrium- stops the accumulation of chloride
What are the important domains associated with CFTR?
12 TMSD- 1 subunit forms the channel
2 nucleotide binding domains- NBD1, NBD2- regulates how the channels open and close
Regulation domain- regulation via phosphorylation by PKA
Most common mutation= deltaF508 in NBD1
What are the classes of CFTR mutation
Class 1 null production Class 2 trafficking Class 3 regulation Class 4 conduction Class 5 partial reduction mRNA
Which classes are associated with more severe CF?
Classes 1-3= CF with pancreatic insufficiency, sweat chloride concs of 100mmol-L-1+
Classes 4,5= CF with pancreatic sufficiency, sweat chloride concs of 70-80
How is CFTR important in the distal colon?
CFTR secretes chloride- determines the water content of the faeces
disrupt Cl secretion- reduce water content- can lead to blockages
What are the 2 receptors associated with colon cells?
Ach- activation leads to a rise in IC Ca- activates K channel on the apical membrane- leads to cl secretion
PGE2- stimulated by binding of prostaglandin, G couplred receptor- leads to increase in cAMP- stimulates PKA- stimulates CFTR
Examples of 4 compounds, their actions and their effect?
Carbachol- ach receptor activation- increase in calcium
indomethacin- inhibits prostaglandin production- reduction in cAMP
IBMX- inhibits PDE- increase in cAMP
Forskolin- activation of cAMP
How is the alveolar model different?
NKCC1 not found in the basolateral membrane- instead a potassium-chloride cotransporter
As a result- very low IC Cl- cl sits below its electrochemical equilibrium
when we open CFTR- get Cl absorption
CF associated with alveolar oedema
How does CF affect the distal sweat glands?
CFTR not working properly- Chloride stays in the sweat- won’t reabsorb Na and CL properly
