lecture 18. CL secretion Flashcards
(20 cards)
Chloride secretion
-Na pump sets up an ion gradient
-The NaK2Cl symporter uses the energy of the Na gradient to
to actively accumulate chloride above its electrochemical gradient
-Cl leaves the cell by passive diffusion through an ion channel
-Na exits via the basolateral Na-pump and K+ via channel
-The transport of Cl across the epithelium induces paracellular Na
and water fluxes
what is the type of water movement in chloride secretion
isotonic
what is the rate limiting step in Cl secretion?
the opening of the Cl channel
what is unique about the Cl channel
The Cl- the channel has been identified at the molecular level as the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) • CFTR overstimulation has been implicated in secretory diarrhea and its dysfunction causes cystic fibrosis
-Only primary transporters can hydrolyze ATP. Cl channel can also hydrolyse ATP but is not a primary transporter!
what causes secretory diahrrea
excessive stimulation of the secretory cells in the crypts of the small intestine and colon
Excessive stimulation could be due to abnormally high concentrations of endogenous secretagogues produced by tumors or inflammation
More commonly it is due to the secretion of enterotoxins from bacteria such as Vibrio cholerae
Enterotoxins irreversibly activate adenylate cyclase causing a maximal stimulation of CFTR lead to a secretion that overwhelms the absorptive capacity of the colon
secretagogues
A secretagogue is an agent that promotes the secretion of hormones, neurohormones, chemical neurotransmitters, enzymes, or other molecules synthesized and secreted by cells.
CFTR
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and chloride channel in vertebrates that is encoded by the CFTR gene.
Molecular mechanism of cholera
Normal:
Neurotransmitters or secretagogues bind G-protein coupled receptors, leading to activation of adenyl cyclase and production of cAMP from ATP. cAMP then phosphorylates CFTR allowing ATP to bind to it and to open→ Cl ions leave the cell( Cl secretion)
Cholera toxin irreversibly activates adenyl cyclase, causing activation of CFTR
Cl→ Na follows→ water follows
What is the treatment for secretory diarrhea?
oral rehydration therapy
cystic fibrosis
• A complex inherited disorder that affects children and young adults
• It is inherited in an autosomal recessive fashion
– Heterozygotes have no symptoms but are carriers
– The child of two carriers has a 1 in 4 chance of getting cystic fibrosis (CF)
• Disease frequency varies among ethnic groups:
– In Northern Europeans 1 in 2500 newborns are affected and 1 in 25 are carriers
– Less common in other ethnic groups
organs affected by cystic fibrosis
involvement of epithelial tissues
clinical management of cystic fibrosis
- Chest percussion to improve clearance of infected secretions
- Antibiotics to treat infections
- Pancreatic enzyme replacement
- Attention to nutritional status
what is the median survival age with cystic fibrosis
late 50s
how does CFTR channel work
CFTR is a Cl channel regulated by protein kinase A-dependent phosphorylation of the R domain and binding of ATP to the NBD( nucleotide-binding domain)
Phosphorylation and ATP binding cause the channel to open and close
what is the main defect/cause of cystic fibrosis?
The defective Cl- channel prevents isotonic fluid secretion and enhances Na+ absorption to give a dry lung surface
no Cl secretion
-dry lung surface increases bacterial proliferation, harder to remove mucus
defective mucociliary clearance
why is salty sweat characteristic of cystic fibrosis
Normally NaCl is reabsorbed in the sweat ducts
The failure of epithelial cells in the ducts of sweat glands to reabsorb NaCl produces the salty sweat in CF patients
In the duct cells the membrane potential is depolarized and Cl- wants to enter the cell down its electrochemical gradient. In CF patients CFTR is defective and Cl- accumulates in the duct lumen and stops Na from getting reabsorbed producing salty sweat
what are the 2 pathways of Cl secretion
- Na/K/Cl pump→ Acetylcholine binds to the basolateral surface receptor and stimulates Ca2+ production within the cell, Ca2+ then assists the exit of Cl through CLCA.
- Na/K/Cl pump→ NA binds to the G-protein coupled receptor on the basolateral side→ stimulating cAMP→ PKA→ phosphorylation of CFTR→ Cl secretion
Hyperpolarisation and depolarization of the membrane
Hyperpolarization is when the membrane potential becomes more negative, while depolarization is when the membrane potential becomes less negative (more positive).
eg depolirization- from -80mV to -60 mV
Cl electrochemical gradient properties
The movement of Cl wants to go in both directions. If they are equal and opposite- no movement of Cl.
If we depolarise the membrane potential and make it less negative–> the conc gradient will take over
If hyperpolarise and make it more negative- the electrical gradient will take over( out of the cell)
Changing the membrane potential- changes the direction of the movement of Cl
At ~ - 80mV the CL is at electrochemical equilibrium
Depolarisation ( eg from -80 to -60mV) will cause chloride to come into the cell
Hyperpolarisation above -80mV will cause CL to leave the cell
How chemical equilibrium can be reached
Every time K+ leaves the cell, it leaves behind a negative charge, making it a little bit harder for the next ion to leave the cell
When the negative charge accumulates the next K+ ion will not leave, stops the movement, as it reaches the electrochemical equilibrium( ~- 80 mV)-resting membrane potential of most cells
