Lecture 24 C4: chloride

Question 1

Describe the process of Chlorine secretion

Answer 1

1. The Na+/K pump sets up ion gradients
2. The NaK-2Cl symporter uses the energy of the Na+ gradient to actively accumulate Cl- above its concentration gradient by bringing in 2CL-, K+ and Na+
3. Cl- exits by passive diffusion down ion channel
4. To maintain the Na+ gradient, Na+ is actively pumped out by Na/K+ pump. K+ exits via ion channel.
5. Na+ and water paracellular transport follow the Cl- to the lumen to make an isotonic secretion

Question 2

How many Kats and Natashas are there and where are they going

Answer 2

2 Kats are being pumped in the cell, 3 natashas are being pumped out of the cell.

Question 3

What is the rate limiting step of chloride secretion

Answer 3

The opening of the Cl- channel to let Cl- exit. This channel is strictly regulated through gating

Question 4

What is the name of the Cl- channel

Answer 4

Cystic Fibrosis Transmembrane conductance Regulator (CFTR)

Question 5

What causes excessive stimulation of CFTR

Answer 5

Abnormally high concentrations of endogenous secretagogues produced by tumours or inflammation. Or entertoxins from bacteria (vibrio cholare)

Question 6

What is the molecular mechanism of cholera

Answer 6

Cholera toxin irreversibly activates adenylate cyclase causing activation of CFTR, bypassing the regulation by g protein. So cAMP is being made which phosphorylates CFTR, leaving it open.

Question 7

What does excessive stimulation of CFTR cause

Answer 7

Secretory diarrhoea where a lot of Cl- is being pumped out which is taking a lot of Na+ and H2O across paracellular, and this secretion overwhelms the reabsorpative capacity of the colon.

Question 8

Where does secretory diarrhoea take place

Answer 8

secretory cells in crypts of the small intestine and colon

Question 9

How do you treat secretory diarrhoea

Answer 9

oral rehydration therapy

Question 10

Who gets cystic fibrosis

Answer 10

Autosomal recessive condition that causes disfunctional CFTR protein that doesn’t let Cl- exit with higher frequency in northern europeans.

Question 11

What organs does cystic fibrosis affect and what is the main cause of mortality

Answer 11

Epithelial tissues in Airways,liver, pancreas, small intestine, reproductive tract. Most die from respiratory failure

Question 12

What is clinical management of CF and median survival age

Answer 12

chest percussion to improve clearance of mucous, antibiotics to treat lung infection. pancreatic enzyme replacement, attention to nutritional status
38 yr old

Question 13

How is CFTR regulated

Answer 13

1. needs phosphorylation of the R domain by protein kinase A
2. Binding of ATP at the nucleotide binding domain

Question 14

Describe how CF defect in CFTR causes thick mucous in lung compared to normal lung

Answer 14

Normally a balance between secretion and absorption of Na+ keeps the lung surface moist but prevents excessive build up of fluid.
Defective CFTR prevents isotonic fluid secretion and enhances Na+ absorption to give a dry lung surface which gets thick mucous difficult to remove.

Question 15

Why does thick mucous cause lung damage

Answer 15

Normally wet mucous is used to trap foreign particles and mucouscillatory escalator. But thick mucous is harder to remove so Bacteria proliferate, immune cells can come and damage healthy tissue, DNA released from bacteria and lung cells adds to stickiness so airways become blocked and deteriorate

Question 16

Describe why people with CF have salty sweat

Answer 16

Formation of sweat is in two stages
- primary isotonic secretion of fluid by acinar cells, and then 2ndary reabsorption of NaCl but not water to make hypotonic solution. But failure of epithelial cells to reabsorb NaCl makes a salty sweat

Question 17

How do you stop water from just coming back with the secondary absorption in normal sweat formation

Answer 17

You block aquaporins the second time

Question 18

Is CFTR active or passive

Answer 18

passive transport. CFTR just mediates its passive diffusion. The direction Cl- goes is based on the electrochemical gradient at the time. Therefore it can be part of the reabsorption of Cl in sweat or letting Cl- out in secretion

Question 19

What are the two steps of salty sweat secretion

Answer 19

Primary isotonic fluid secretion by Acinar cells. 2ndary reabsorption of NaCL but not water so hypotonic solution.

Question 20

Are the duct cells hyperpolarised or depolarised after primary secretion

Answer 20

They are depolarised - making Cl- want to go back inside.