Lecture 18: Chloride Secretion

Question 1

Describe the process of chloride secretion in the small intestine

Answer 1

1. Epithelial cells divided into apical (lumen) and basolateral (blood) membrane domains
2. Na+/K+ primary active transporter pump in the basolateral membrane sets up high Na+ conc. in the blood
3. Na+, K+ and 2 Cl- ions diffuse down conc. gradient into the epithelial cells via a secondary passive NaK2Cl symporter in the basolateral membrane
4. Cl- leaves cell to lumen by passive diffusion through an ion channel called cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane
5. Na+ exits cell to blood through Na/K pump and K+ leaves through an ion channel in the basolateral membrane
6. The transport of Cl- across the epithelium causes movement of Na+ and water from blood to lumen via paracellular pathway (isotonic fluid secretion)

Question 2

What is the rate limiting step of chloride secretion?

Answer 2

The opening of the Cystic Fibrosis Transmembrane conductance regulator as the Cl- ions accumulated in the epithelial cells cannot leave if the CFTR remains gated

Question 3

How is secretory diarrhoea caused?

Answer 3

Excessive stimulation of the secretory cells in the crypts of the small intestine and colon

Question 4

How are the secretory cells of the small intestine over stimulated?

Answer 4

Abnormal high concentration of secretagogues produced by tumours or inflammation

Secretion of enterotoxins from bacteria such as Vibrio Cholerae

Question 5

What are secretagogues?

Answer 5

Neurotransmitters that stimulate secretion of Cl- ions by binding to GPCR causing the activation of adenylate cyclase via a G protein

Question 6

What are enterotoxins?

Answer 6

Toxins produced by bacteria such as Vibrio Cholerae that bind to adenylate cyclase enzyme directly causing irreversible maximal stimulation of CFTR

Question 7

How can secretory diarrhoea be treated?

Answer 7

Caused from over secretion -> therefore increase absorption

This can be done by oral rehydration therapy

Question 8

What is cystic fibrosis?

Answer 8

An inherited disorder which affects epithelial tissues leading to many different symptoms

Common in Europeans

Inherited in an autosomal recessive fashion

Question 9

How can cystic fibrosis affect the airways?

Answer 9

Clogging and infection of bronchial passage impedes breathing. Infections could lead to loss of respiratory function of lungs leading to death (most common cause of death due to cystic fibrosis)

Question 10

How can cystic fibrosis affect the liver?

Answer 10

Plugging of bile ducts impedes digestion and disrupts liver function

Question 11

How can cystic fibrosis affect the pancreas?

Answer 11

Critical digestive enzymes cannot be delivered to bowel - can lead to diabetes if beta cells are affected

Question 12

How can cystic fibrosis affect the small intestine?

Answer 12

Obstruction of gut by thick stool means surgery is needed

Question 13

How can cystic fibrosis affect the reproductive tract?

Answer 13

No fine ducts leading to male infertility. Blocking of mucous from sperm entering causes female infertility also.

Question 14

How can cystic fibrosis affect the skin?

Answer 14

Excessive salt in sweat

Question 15

How can cystic fibrosis be diagnosed?

Answer 15

Excessive salt in sweat

Question 16

How can cystic fibrosis be treated?

Answer 16

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

Question 17

How is the CFTR regulated?

Answer 17

A protein kinase at the end of a phosphorylation cascade causes a phosphate to bind to the regulatory domain allowing ATP to bind to the nucleotide binding domains -> this causes the channel to become ungated

Question 18

What happens across the layer of epithelial cells between the airway and blood in a normal lung?

Answer 18

A balance between secretion and absorption keeps lung surface moist (optimal amount of water) preventing too much fluid build up

Question 19

What happens across the layer of epithelial cells between the airway and blood in a lung affected by cystic fibrosis?

Answer 19

The defective Cl- channel prevents isotonic fluid secretion and enhances Na+ absorption to give a dry lung surface

Question 20

How does a dry lung surface affect mucous?

Answer 20

The mucous lining the airway becomes thick and difficult to remove - this causes bacteria to proliferate and attract immune cells damaging airway

Question 21

How is sweat produced?

Answer 21

1. A primary isotonic secretion of fluid
2. A secondary reabsorption of NaCl but not water producing a hypotonic solution in which the water potential is higher outside of the cell

Question 22

Why does cystic fibrosis lead to salty sweat?

Answer 22

The failure of epithelial cells in the ducts of sweat glands to reabsorb NaCl means sweat contains higher salt content