Lecture 18 Chloride Transport

Question 1

What is the NaK2Cl symporter?

Answer 1

It brings in 1 Na+ ion, 1 K+ ion and 2 Cl- ions

Question 2

What is the rate limiting step in chloride secretion?

Answer 2

The opening of the Cl- channel, as it is strictly regulated. This means that even if Cl- is above electrochemical equilibrium, it cannot leave the cell unless the channel is open

Question 3

What is secretory diarrhea?

Answer 3

It is caused by excessive stimulation of secretory cells in the crypts of the small intestines and colon

Question 4

What causes excessive stimulation of secretory cells?

Answer 4

Abnormally high concentrations of endogenous secretagogues produced by tumours or inflammation
Secretion of enterotoxins from bacteria such as Vibrio cholera

Question 5

How do enterotoxins work?

Answer 5

They irreversibly activate adenylyl cyclase causing maximum stimulation of CFTR which leads to a secretion that overwhelms the absorptive capacity of the colon

Question 6

What is the molecular mechanism of cholera?

Answer 6

Normally, secretagogue binds GPCR which causes G protein to activate adenylate cyclase which causes ATP–> cAMP which causes protein kinase A to phosphorylate CFTR which causes it to open
Cholera irreversibly activates adenylate cyclase causing activation of CFTR

Question 7

How can secretory diarrhoea be treated?

Answer 7

Crypt cells are stem cells so keep dividing, eventually reaching the villus and dying off. The functions of the cells changes as it moves upwards, going from secretory cells to absorptive cells. This means that up-regulation of absorption (oral rehydration therapy) over 5 days can treat cholera, as there would be a whole new gut lining

Question 8

How is cystic fibrosis inherited?

Answer 8

Inherited in autosomal recessive fashion, heterozygotes have no symptoms but are carriers.

Question 9

How does cystic fibrosis vary among different ethnic groups

Answer 9

In Northern Europeans, 1/2500 newborns are affected and 1/25 are carriers. Less common in other ethnic groups.

Question 10

How are the lungs affected in cystic fibrosis?

Answer 10

Clogging and infection of bronchial passages impedes breathing. Infection destroys the lungs.

Question 11

How is the liver affected during cystic fibrosis

Answer 11

Small bile ducts are clogged which impedes digestion (5% of patients)

Question 12

How is the pancreas affected in cystic fibrosis?

Answer 12

Ducts are blocked which prevents pancreas from delivering critical pancreatic enzymes to bowels, can result in diabetes. (85% of patients)

Question 13

How is the small intestines affected

Answer 13

Obstruction of the gut by thick stool necessitates surgery in around 10% of newborns

Question 14

How is the reproductive tract affected by cystic fibrosis?

Answer 14

Absence of fine ducts such as the vas deferens renders 95% of males infertile. Occasionally women are made infertile by dense plug of mucus that blocks sperm from entering the uterus

Question 15

What is a common theme in the symptoms of cystic fibrosis?

Answer 15

They all involve epithelial tissues

Question 16

What causes most mortalities in cystic fibrosis patients, and what is the median survival age?

Answer 16

Breathing difficulty, median survival age is 38 years of age

Question 17

What are clinical management of cystic fibrosis?

Answer 17

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

Question 18

What is the CFTR?

Answer 18

Protein kinase A phosphorylates the R domain which causes it to detach from blocking the channel. This allows the binding of ATP, and the energy generated from hydrolysis opens the channel.

Question 19

What is the mechanism of secretion and absorption of Cl- in a normal lung?

Answer 19

There is a balance between secretion and absorption which keeps the lung surface moist but prevents excessive fluid buildup

Question 20

What is the mechanism of secretion and absorption of lung epithelial cells in CF?

Answer 20

There is no isotonic fluid secretion due to defective CFTR channels, sodium reabsorption is enhanced which gives a dry lung surface

Question 21

What happens to the mucous in CF?

Answer 21

Because the lung surface is dry the mucous becomes sticky instead of acting as a conveyor belt. This becomes a place for bacteria to aggregate which causes inflammation and damage to cells in the airway. This means lung capacity decreases and a lung transplant is required.

Question 22

What is the Cl- secretion pathway?

Answer 22

CFTR gene defect –> Defective ion transport –> Airway surface liquid depletion –> Defective mucocillary clearance –> Mucus obstruction, inflammation and infection

Question 23

How does formation of sweat normally work?

Answer 23

A primary isotonic secretion and a secondary reabsorption of ions, producing a hypotonic solution

Question 24

Why is sweat salty in CF patients?

Answer 24

Epithelial cells fail to reabsorb NaCl, resulting in salty sweat

Question 25

What is sweat formation in CF patients?

Answer 25

In secretory coil 2 Cl- channels (CLCA and CFTR) which forms the isotonic solution

In the reabsorptive ducts, electric potential is depolarised and Na+ and Cl- comes down its electrochemical gradient. These cells do not have aquaporins and tight junctions which means water is not reabsorbed.