CP - Traffic across epithelial cells: Chloride secretion

Question 1

In chloride secretion, where is the cotransporter located?

Answer 1

In the basolateral membrane

Question 2

In chloride secretion, what does the cotransporter do?

Answer 2

Accumulates chloride above its electrochemical equilibrium, which enables chloride to leave the cell via a chloride channel located in the apical membrane

Question 3

In chloride secretion, how does sodium move?

Answer 3

Moves via the paracellular pathway to preserve electroneutrality

Question 4

In step 1 of chloride secretion, what separates the cells into apical and basolateral membrane domains?

Answer 4

Tight junctions

Question 5

In step 2 of chloride secretion, what does the Na/K pump in the basolateral membrane set up?

Answer 5

Ion gradients

Question 6

In step 3 of chloride secretion, what does the NaK2Cl symporter do?

Answer 6

It uses the energy of the Na+ gradient to actively accumulate chloride above its conc. gradient. It carries mediated transport and secondary active transport which, allows Na+ to diffuse down its electrochemical gradient into the cell and pull with it 2 Cl- ions and 1 K+ ion so have 2 +ve charges and 2 -ve charges (electroneutral)

Question 7

In step 4 of chloride secretion, how does Cl- leave the cell?

Answer 7

By passive diffusion down its electrochemical gradient, through an ion channel in the apical membrane, into the lumen

Question 8

In step 5 of chloride secretion, how does Na+ exit?

Answer 8

Na+ exits via the basolateral Na/K pump down its electrochemical gradient and the Na/K pump uses the energy to maintain this Na gradient which is driven by the uptake of Cl and K above their electrochemical gradient

Question 9

In step 5 of chloride secretion, how does K+ exit?

Answer 9

K+ exits via its channel diffusing down its electrochemical gradient. This has an effect on steepening the gradient for Cl- exit as it makes the cell membrane potential more -ve and the more -ve the environment, the more Cl- wants to leave

Question 10

In step 6 of chloride secretion, what does the transport of Cl- across the epithelium do?

Answer 10

It induces paracellular Na+ and water fluxes as when Cl- leaves the cell, it attracts a Na+ ion and the movement of Na+ and Cl- creates an osmotic difference which causes water to move as well

Question 11

In chloride secretion, if the Cl- ion channel is closed, what happens? What also happens as soon as it opens?

Answer 11

There is no movement of Na+, Cl- and water so, no Cl secretion as there’s no gradient for secretion, even though Cl- is accumulated above electrochemical gradient. As soon as it opens, since its above electrochemical gradient, Cl- flows out, Na+ and water comes via paracellular pathway, have isotonic fluid secretion (changing the gating of CFTR from open to close)

Question 12

The opening of the Cl- channel is strictly _____

Answer 12

regulated (gated)

Question 13

What is the rate limiting step in chloride secretion?

Answer 13

The opening of the Cl- channel

Question 14

At molecular level, the Cl- channel has been identified as the?

Answer 14

Cystic Fibrosis Transmembrane conductance Regulator (CFTR)

Question 15

What happens when CFTR is overly stimulated?

Answer 15

It has been implicated in secretory diarrhea and its dysfunction causes cystic fibrosis

Question 16

How is secretory diarrhea caused?

Answer 16

By excessive stimulation of the secretory cells in the crypts of the small intestine and colon. Due to being over stimulated, pump out a lot of Cl-, Na+ and water which, exceeds capacity to reabsorb that fluid resulting in a lot of fluid in gut

Question 17

What could be the causes of the excessive stimulation leading to secretory diarrhea?

Answer 17

Could be due to abnormally high conc. of endogenous secretagogues produced by tumours or inflammation which can open this Cl- channel

Question 18

What is the more commonly cause of secretory diarrhea?

Answer 18

The secretion of entertoxins from bacteria, e.g. Vibrio Cholerae as the enterotoxins irreversibly activate adenylate cyclase, causing a maximal stimulation of CFTR, lead to a secretion that overwhelms the absorptive capacity of the colon

Question 19

What is the molecular mechanism of cholera?

Answer 19

Secretagogue binds to the G-protein coupled receptor and releases a G-protein. This binds to adenylate cyclase, along with the cholera toxin irreversibly bindingto it, causing activation of CTFR, producing lots of cAMP (from the conversion of ATP) and phosphorylates CFTR and channel stays open permanently

Question 20

What is the result of the molecular mechanism of cholera?

Answer 20

The channel stays open permanently as the rate limiting step is gone, so all of the ion gradients are accumulating Cl- into the cell. Cl- is immediately leaving via CFTR due to having an open ion channel that is effectively allowing pumping of fluid out of the body and it overcomes the ability to reabsorb that fluid

Question 21

In chloride secretion, what do secretagogues do?

Answer 21

They bind to the receptors in the basolateral membrane to activate signalling pathways that activate CFTR in the apical membrane

Question 22

How secretory diarrhea treated?

Answer 22

Oral rehydration therapy (give people clean water with salt and glucose) stimulate isotonic fluid uptake to counter secretory diarrhea (offset some of the effects of over stimulation by increasing water influx) induced by the infection

Question 23

What is cystic fibrosis?

Answer 23

A complex inherited disorder that affects children and young adults. It’s inherited in autosomal recessive fashion. Heterozygotes have no symptoms but are carriers (the child of 2 carriers have a 1/4 chance of getting it)

Question 24

What are the organs affected by cystic fibrosis?

Answer 24

The chloride channel responsible for chloride exit is defective. This causes a diverse range of clinical symptoms which depend on the location of the epithelial tissues involved. Most causes of mortality is due to respiratory failure

Question 25

What is the clinical management of cystic fibrosis?

Answer 25

• Chest percussion to improve clearance of infected secretions
• Antibiotics to treat infections
• Pancreatic enzyme replacement
• Attention to nutritional status

Question 26

How does the CFTR work?

Answer 26

CFTR is an Cl channel regulated by protein kinase A dependent phosphorylation of the R domain and binding and hydrolyzing of ATP to the nucleotide binding domains (there are 2). When this happens, it’s like a ligand-gated interaction which, causes the R domain to move out of the pore and for ions to diffuse down the electrochemical gradient and to leave the cell

Question 27

How does cystic fibrosis cause a defect in Cl- secretion?

Answer 27

In patients with cystic fibrosis, the defective Cl- channels prevents isotonic fluid secretion and enhance Na+ absorption to give a dry lung surface

Question 28

How does blocking the Cl- secretion contribute to lung pathology?

Answer 28

mucus becomes thick and difficult to remove so bacteria proliferate, airways become plugged, etc and a lot less surface area for gas exchange

Question 29

How does cystic fibrosis affect sweat formation?

process (2 steps)

Answer 29

People with cystic fibrosis have very salty sweat.
Formation of sweat is a 2 stage process:
1. A primary isotonic secretion of fluid by acinar cells
2. A secondary reabsorption of NaCl to produce a hypotonic solution (as what comes out at the surface is a solution where NaCl is reabsorbed to make it have less salt and more water)

Question 30

Why do people with cystic fibrosis have very salty sweat?

Answer 30

The failure of epithelial cells in the ducts of sweat glands to reabsorb NaCl produces the salty sweat (CFTR is defective and Cl- accumulates in the duct lumen as there’s no movement of Cl- which, affects the movement of Na+)

Question 31

In sweat glands, the absence of aquaporins in the apical membrane of duct cells can cause what?

Answer 31

The absence of aquaporins in the apical membrane of duct cells drive water absorption to produce a hypotonic sweat

Question 32

In the sweat glands, in the epithelial duct cells, the membrane potential is ______ and ____ wants to enter the cell down its _____ ______

Answer 32

depolarised, Cl-

electrochemical gradient