Chloride Secretion and Cystic Fibrosis

Vocabulary flashcards for Chloride Secretion and Cystic Fibrosis lecture.

Tight Junctions

Divide epithelial cells into apical and basolateral membrane domains.

Apical Membrane Domain

The surface of an epithelial cell that faces the outside or lumen.

Basolateral Membrane Domain

The surface of an epithelial cell that faces the inside or blood.

Na/K ATPase Pump

An active transporter that uses ATP hydrolysis to move 3 Na ions out and 2 K ions into the cell.

Electrochemical Gradient

The driving force for ion movement based on both concentration and electrical potential differences.

NaK2Cl Symporter

A secondary active transporter that uses the Na gradient to accumulate chloride above its electrochemical gradient.

Symport/Cotransport

Carrier-mediated transport where all ions move in the same direction.

Electroneutral Transport

Transport of ions that maintains electrical neutrality (e.g., 1 Na, 1 K, and 2 Cl).

Passive Diffusion

Movement of a substance across a membrane down its electrochemical gradient through an ion channel.

Pump-Leak Hypothesis

Maintaining ion gradients for Cl secretion by actively removing Na and allowing K diffusion to maintain membrane potential.

Paracellular Flux

Movement of substances between epithelial cells, driven by electrical and osmotic gradients.

Isotonic Fluid Secretion

Movement of fluid from one side of a tissue to another with the same composition as body fluids.

Secondary Active Transport

Using the energy of an ion gradient (e.g., Na) to transport another substance against its gradient.

Rate-Limiting Step

The slowest step in a process that determines the overall rate.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

A chloride channel that regulates Cl secretion and is defective in cystic fibrosis.

Secretory Diarrhea

Diarrhea caused by excessive stimulation of secretory cells in the crypts of the small intestine and colon.

Enterotoxins

Toxins secreted by bacteria (e.g., Vibrio cholerae) that can cause excessive Cl secretion.

Adenylate Cyclase

An enzyme that produces cAMP in response to cell signaling pathways.

cAMP

A second messenger that activates protein kinase A and leads to phosphorylation of CFTR.

G-Coupled Protein Receptor

A receptor that activates adenylate cyclase via a G protein in response to secretagogues.

Protein Kinase A

An enzyme that phosphorylates CFTR, leading to the opening of the Cl channel.

Crypt Cells

Epithelial cells in the crypts of the small intestine that are responsible for Cl secretion.

Villus Cells

Epithelial cells in the villi of the small intestine that are responsible for glucose absorption.

Oral Rehydration Therapy

Treatment for secretory diarrhea that involves replacing lost fluids and electrolytes orally.

Cystic Fibrosis

A complex inherited disorder caused by a defect in CFTR, affecting multiple organ systems.

Autosomal Recessive

Inheritance pattern where heterozygotes are carriers and the child of two carriers has a 1 in 4 chance of getting the disease.

Heterozygote

An individual carrying one copy of a mutated gene and one normal copy.

Chest Percussion

A technique used to improve clearance of infected secretions in cystic fibrosis patients.

Pancreatic Enzyme Replacement

Supplementation of pancreatic enzymes to aid digestion in cystic fibrosis patients.

R-Domain

Regulatory domain of CFTR that is phosphorylated by protein kinase A.

NBD (Nucleotide Binding Domain)

Domain in CFTR that binds ATP, causing a conformational change that opens the channel.

Lung Epithelial Cells (Normal)

Maintain a balance between secretion and absorption to keep the lung surface moist.

Lung Epithelial Cells (CF)

Defective Cl channel prevents isotonic fluid secretion and enhances Na absorption, leading to a dry lung surface.

Acinar Cells

Cells that perform primary isotonic secretion of fluid in sweat glands.

Reabsorptive Duct Cells

Cells that reabsorb NaCl but not water to produce hypotonic sweat.

Hypotonic Solution

A solution with more fluid and less solute (e.g., sweat).

Depolarized

When the chloride wants to enter the cell through its electrochemical gradient.

Na pump

The sodium is the electrochemical gradient for Na to diffuse down, it accumulates K and 2 Cl, and the Cl can diffuse through CFTR when this channel is stimulated by a secretagogue

Neural epinephrine/adrenaline

Example of Cl secretion - theres a sodium pump in the middle which is the electrochemical gradient for Na to diffuse down, it accumulates K and 2 Cl, and the Cl can diffuse through CFTR when this channel is stimulated by a secretagogue.

Acetyl choline

Regulated by acetyl choline (ACl), stimulated by InsP3 (IP3) to increase Ca, and this creates a Ca sensitive Cl channel

InsP3

Regulated by acetyl choline (ACl), stimulated by InsP3 (IP3) to increase Ca, and this creates a Ca sensitive Cl channel

IP3

Regulated by acetyl choline (ACl), stimulated by InsP3 (IP3) to increase Ca, and this creates a Ca sensitive Cl channel

Na channel

allows Na to diffuse down its electrochemical gradient and then the Na is removed by the Na/K ATPase, and the Cl comes in via CFTR

Electrochemical gradient of Cl in small intestine

If the electrochemical gradient for Cl in the small intestinal cells, is such that Cl wants to leave, then Cl will diffuse down its electrochemical gradient and leave the cell.

Cl-Channel

CFTR is a Cl channel regulated by protein kinase A, dependant phosphorylation of the R-domain and binding of ATP to the NBD which causes the channel to open so Cl can diffuse down its electrochemical gradient.

Chloride

Electroneutral transport ion.

Potassium

Electroneutral transport ion.

Sodium

Electroneutral transport ion.

Cl channel

Over stimulation has been implicated in secretory diarrhea and its dysfunction causes cystic fibrosis.

Enterotoxins irreversibly activate

cell signaling pathway which involves the activation of adenylate cyclase to produce cAMP.

Stem cells

In the crypt cells.

CFTR transmembrane protein

Has properties of a channel, creating a pore across the membrane, but it has nucleotide binding domains.

Transmembrane protein

CFTR is supposed to be a Cl channel but it has properties of a pump (binds ATP).

Regulatory domain

Can sit into a pore and close the channel.

Transmembrane conductance regulator

Thought to be regulating the movement of Cl across the channel rather than mediating it.

Balance for lung epithelial cells

A balance between secretion and absorption keeps the lung surface moist but prevents excessive fluid build up.

SWEAT FORMATION

primary isotonic secretion of fluid by acinar cells & secondary reabsorption of NaCl but NOT water produces a hypotonic solution

Normal sweat formation: Acinar cells

A primary Cl secretion

Normal sweat formation: reabsorptive duct cells

Cells that produce hypotonic sweat.

Concentration of Cl

Governs electrochemical gradient.

Electrical membrane potential

Governs electrochemical gradient.

Depolarised Membrane Potential

Is when Cl can diffuse down the electrochemical gradient into a less negative environment.

Hyperpolarized Membrane Potential

Cl leaves.

The function of the Cl channel is strictly:

Regulated/gated.

Small intestine

Blockage here can occur in patients that are affected with cystic fibrosis.

The pancreas

can get occlusion of the ducts and a breakdown of pancreatitis of patients that are affected with cystic fibrosis.

The liver

Blocking of the small ducts in the bile tubes

The airways

There is a clogging/blocking of the breathing passages which causes a lot of mucous and infection in the lungs, causing respiratory insufficiency

The skin

Very salty sweat, due to cystic fibrosis.

Villus

Absorption

Crypt

Secretion

CFTR defect

Cl accumulates in the duct lumen producing salty sweat.

Median survival

38

Molecular level CFTR

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Northern europeans newborns CF

1 in 2500 newborns are affected and 1 in 25 are carriers.

Treatment towards Secretory Diarrhoea Consists of:

Oral Rehydration Therapy

Endogenous secretagogues

Produced by tumors or inflammation.

Enterotoxins

From bacteria such as Vibrio cholerae.