Lecture 18: Chloride Secretion Flashcards
Describe the process of chloride secretion in the small intestine
- Epithelial cells divided into apical (lumen) and basolateral (blood) membrane domains
- Na+/K+ primary active transporter pump in the basolateral membrane sets up high Na+ conc. in the blood
- Na+, K+ and 2 Cl- ions diffuse down conc. gradient into the epithelial cells via a secondary passive NaK2Cl symporter in the basolateral membrane
- Cl- leaves cell to lumen by passive diffusion through an ion channel called cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane
- Na+ exits cell to blood through Na/K pump and K+ leaves through an ion channel in the basolateral membrane
- The transport of Cl- across the epithelium causes movement of Na+ and water from blood to lumen via paracellular pathway (isotonic fluid secretion)
What is the rate limiting step of chloride secretion?
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
How is secretory diarrhoea caused?
Excessive stimulation of the secretory cells in the crypts of the small intestine and colon
How are the secretory cells of the small intestine over stimulated?
Abnormal high concentration of secretagogues produced by tumours or inflammation
Secretion of enterotoxins from bacteria such as Vibrio Cholerae
What are secretagogues?
Neurotransmitters that stimulate secretion of Cl- ions by binding to GPCR causing the activation of adenylate cyclase via a G protein
What are enterotoxins?
Toxins produced by bacteria such as Vibrio Cholerae that bind to adenylate cyclase enzyme directly causing irreversible maximal stimulation of CFTR
How can secretory diarrhoea be treated?
Caused from over secretion -> therefore increase absorption
This can be done by oral rehydration therapy
What is cystic fibrosis?
An inherited disorder which affects epithelial tissues leading to many different symptoms
Common in Europeans
Inherited in an autosomal recessive fashion
How can cystic fibrosis affect the airways?
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)
How can cystic fibrosis affect the liver?
Plugging of bile ducts impedes digestion and disrupts liver function
How can cystic fibrosis affect the pancreas?
Critical digestive enzymes cannot be delivered to bowel - can lead to diabetes if beta cells are affected
How can cystic fibrosis affect the small intestine?
Obstruction of gut by thick stool means surgery is needed
How can cystic fibrosis affect the reproductive tract?
No fine ducts leading to male infertility. Blocking of mucous from sperm entering causes female infertility also.
How can cystic fibrosis affect the skin?
Excessive salt in sweat
How can cystic fibrosis be diagnosed?
Excessive salt in sweat
How can cystic fibrosis be treated?
Chest percussions to improve clearance of infected secretions
Antibiotics to treat infections
Pancreatic enzyme replacement
Attention to nutritional status
How is the CFTR regulated?
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
What happens across the layer of epithelial cells between the airway and blood in a normal lung?
A balance between secretion and absorption keeps lung surface moist (optimal amount of water) preventing too much fluid build up
What happens across the layer of epithelial cells between the airway and blood in a lung affected by cystic fibrosis?
The defective Cl- channel prevents isotonic fluid secretion and enhances Na+ absorption to give a dry lung surface
How does a dry lung surface affect mucous?
The mucous lining the airway becomes thick and difficult to remove - this causes bacteria to proliferate and attract immune cells damaging airway
How is sweat produced?
- A primary isotonic secretion of fluid
- A secondary reabsorption of NaCl but not water producing a hypotonic solution in which the water potential is higher outside of the cell
Why does cystic fibrosis lead to salty sweat?
The failure of epithelial cells in the ducts of sweat glands to reabsorb NaCl means sweat contains higher salt content
