Lecture 18: Traffic across epithelial cells: Chloride secretion

Na+/K+ ATPase Pump Function

Helps establish ion gradients (2K+ and 3Na+)

Na-K-2Cl symporter Function

Actively accumulates chloride above its electrochemical gradient using energy from the Na+ gradient

Chloride Channel Function

Allows chloride to leave the cell via passive diffusion

CTFR Function

Cystic Fibrosis Transmembrane conductance regulator is a protein that acts as a chloride channel, it is highly regulated by protein kinase and casues ATP to bind to the nucleotide-binding domain (NBD) which opens the channel and chloride this can diffuse down it’s concentration gradient.

Chloride Secretion 6 steps and rate limiting step

1. Tight junctions divide cells into apical and basolateral membrane domains

2. Na+/K+ ATPase pump creates ion gradients

3. Na-K-Cl symporter accumulates chloride

4. Chloride exits through the chloride channel

5. Na+ exits via basolateral pump Na+ pump, K+ exits via channels

6. Chloride transport causes paracellular Na+ and water fluxes

   -Accumulation and opening of chloride channel is the rate-limiting step

Secretory Diarrhea Function and it’s triggers

It’s caused by excessive stimulation of the secretory cells in the crypts of the small intestine and colon, this results in secretion overwhelming the absorptive cavity of the colon

Cholera Function

Cholera toxin irreversibly activates adenylate cyclase leading to CTFR activation. This process involves a G-protein coupled receptor and results in increased cAMP levels, this leads to phosphorylation and activation of CFTR and thus sustained secretion.

Oral Rehydration Therapy for secretory Diarrhea caused by cholera

It utilizes glucose-stimulated water flux to aid in reabsorption. A possible issue is is overstimulation of secretion.

Cystic Fibrosis (CF) Function

A complex inherited disorder affecting children and young adults. It’s inherited in an autosomal recessive fashion. Disease frequency varies among ethnic groups. Patients with CF have a variety of symptoms however, one common theme is no matter the organ epithelial tissue is involved. Most cases of mortality are respiratory failure.

Normal lung epithelial cells vs Lung epithelial cells in CF

Normal lung epithelial cells has balance between secretion and absorption which maintains lung surface moisture without excessive fluid build up

Lung epithelial cells in cystic fibrosis, chloride channel becomes defective preventing isotonic fluid secretion and enhances Na+ absorption resulting in dry lung surface causing mucus to be thick and hard to remove causing damage to healthy tissue.

Cystic Fibrosis and 2-step sweat formation

1. Primary isotonic secretion of fluid by acinar cells

2. Secondary reabsorption of NaCl (not water) in the ducts producing a hypotonic solution

   -In CF epithelial cells in ducts of sweat glands fail to reabsorb NaCl leading to salty sweat

Normal Sweat formation 2 steps

1. Primary secretion occurs in the secretory coil driven by parasympathetic stimulation (ACh)

2. Secondary reabsorption occurs in the reabsorptive duct driven by sympathetic stimulation (Na)