Physiology Lecture 18: Chloride Secretion and Transport

Cellular Mechanisms of Chloride Secretion

• Tight junctions divide cells into apical and basolateral domains
• Na pump sets up ion gradients through primary active transport, hydrolyzing ATP to move 3 sodium ions against its chemical gradient and accumulate 2 potassium ions inside the cell
• The Na Cl symporter uses the energy of the Na gradient to actively accumulate chloride above its electrochemical gradient, an example of a secondary active transporter

Chloride Transport Across the Epithelium

• Chloride enters the cell through the Na Cl symporter and exits the cell by passive diffusion through the CFTR ion channel
• Na exists through the basolateral Na-pump and K+ via channel
• The transport of Cl across the epithelium induces paracellular Na and water fluxes

Rate Limiting Step of Chloride Secretion

• The chloride channel (CFTR) is the rate limiting step of chloride secretion, as chloride can't leave the cell unless the chloride channel is open
• The opening of the Cl- channels is strictly gated (regulated)

CFTR and Its Role in Diseases

• CFTR is recognized as the Cystic Fibrosis Transmembrane conductance Regulator
• Overstimulation of CFTR can cause secretory diarrhea, while its dysfunction causes cystic fibrosis

Secretory Diarrhea

• Caused by overactive secretory cells in the crypts of the small intestine and colon
• Overactivity can be caused by high concentrations of endogenous secretagogues produced by tumors or inflammation
• Secretagogues are neurotransmitters or hormones that cause epithelial cells to stimulate signalling pathways, which open the chloride channel, CFTR, and start the process of secretion
• Most commonly caused by the secretion of Enterotoxins from bacteria such as Vibrio cholerae

Molecular Mechanism of Cholera

• Secretagogue binds to the G protein coupled receptor, activating adenylate cyclase, which converts ATP to cAMP, and activates protein kinase A to phosphorylate the CFTR channel, causing it to open
• Cholera toxin activates adenylate cyclase, which continues and doesn't stop, activating the CFTR

Treating Secretory Diarrhea

• The problem with secretory diarrhea is that the secretion becomes overstimulated, overwhelming the ability of the colon to do normal absorption
• Treatment involves increasing absorption, which can be done by using glucose stimulated water fluxes, such as oral rehydration therapy to prevent dehydration