Chloride secretion Flashcards
Label the diagram and explain the steps happening from 1-6. Where can this occur?
Occur in the small intestine, mouth, skin etc.
How do tight junctions divide the cells into apical and basolateral membrane domains?
Prevent the movement of proteins from these domains
What type of transport is the Na/K pump?
Carrier mediated transport that is active primary transport
What does the Na/K pump move and where to?
3Na+ out of the cell and 2K+ into the cell
Where does the chloride moving into the epithelial cell come from?
The blood
What kind of transporter is used to move chloride into the epithelial cell? What particles are involved? Why?
A secondary transporter, NaK2Cl symporter Na+, K+ and 2Cl- all move into the cell Cl- has to be moved against its electrical gradient (not electrochemical gradient as it is moving down its concentration gradient)
In the NaK2Cl symporter, how does each particle move against its electrochemical gradient?
Na+ moves with it K+ moves against it Cl- is moving against its electrical gradient but with its concentration gradient (electrochemical gradient is not relevant for this one)
What is the net movement of Na+ and K+ during chloride secretion? Exlaine
There is no next movement Na+ and K+ get pumped out by Na/K pump but the Na+ is then transported back in by NaK2Cl symporter, K+ diffuses out via K+ ion channel
Once the Cl- is pumped into the cell by the NaK2Cl symporter, what happens to it?
It diffuses out of the cell by a Cl- ion channel on the apical membrane
How does the diffusion of Cl- on the apical membrane influence charge in what region?
It makes the lumen more negatively charged
What does a change in the change of the lumen cause? How is this restored?
Disrupts the electroneutrality of the lumen (makes it more negatively charged) Positively charged ions (e.g. Na+) restore electroneutrality
How do the positively charged ions move into the lumen? What does this require?
Move via paracellular transport Requires leaky tight junctions
Once Na+ and Cl- have moved into the lumen, what does this create? What is the response to this?
A local osmotic difference Water moves to restore osmotic equilibrium
How does water move into the lumen?
By aquaporins
What is the water that is secreted during chloride secretion used for?
Lubrication of the intestinal tract, aqueous solution for enzyme action
How much water can be secreted a day in the gut?
9L
How is the water reabsorbed into the body
Glucose absorption
How is secretion of water controlled? What does this make this component?
The Cl- ion channel on the apical membrane is strictly regulated by gating Makes Cl- ion channel a rate limiting step
What happens if the Cl- ion channel is not controlled?
If it is not controlled and therefore remains open then a person can dehydrate very rapidly
What can stimulate the Cl- channel? (just some examples)
Hunger (mouth water), anxiety (sweating)
What is the name of the Cl- channel?
Cystic Fibrosis Transmembrane conductance Regulator (CFTR)
Who has CFTR?
Everyone (it is the normal operating ion channel)
What happens when CFTR is overstimulated and inhibited?
Overstimulated = diarrhoea Inhibited = cystic fibrosis
What causes secretory diarrhoea?
Excessive estimation of the secretory cells in the crypts of the small intestine and colon (glands imbedded within gut wall)
What makes secretory cells in the crypts of the gut excessively stimulated?
Abnormally high concentration of endogenous (internal FYI) secretagogues
What are secretagogues
Peptide hormones that regulate the CFTR
What causes high concentration of endogenous secretagogues?
Tumours, inflammation or bacterial infection
What viral infection commonly causes overstimulation of CFTR?
Vibrio cholerae
How does Vibrio cholerae cause overstimulation of CFTR?
Enterotoxins attack the CFTR by irreversibly activating adenylate cyclase causing maximal stimulation of CFTR
How does overstimulation of CFTR cause diarrhoea?
Overwhelms the absorptive capacity of the colon so most of the water is not absorbed
What does adenylate cyclase do? How does this contribute to the activation of CFTR?
Activates cAMP cAMP is used as a secondary messenger in a lot of reactions
Where do secretagogues come from?
Nerve terminals or form the circulatory system
What do secretagogues do?
Bind to G-protein coupled receptor which is used to activate cAMP pathway
How does the cAMP activate CFTR?
cAMP activates protein kinase A which then phosphorylates CFTR activating it
How do enterotoxins produced by cholera activate CFTR?
The enterotoxin fits the active site of Adenylate cyclase, bypassing the G protein receptor activator pathway. This then activates the cAMP pathway leading to phosphorylation of CFTR and activation
How does the activation of cAMP from cholera and G-protein differ?
Cholera causes irreversible activation of cAMP pathway while G-protein is just temporary
What does irreversible activation of the cAMP pathway result in?
Results in CFTR gate being constantly open therefore constant movement of Cl- ions into the lumen, constant movement of Cl- therefore Na+ and H2O constantly flow out of blood as well resulting in severe dehydration
How much water can someone with cholera toxin secretory diarrhoea lose in three days?
20L
What is the treatment for secretory diarrhoea? Explain the treatment
Constant rehydration and prevent re-infection The crypt cells that are infected, over a period of 5 days, migrate up from their groove and form villus that are then are discarded. As long as the patient does not get reinfected and does not die from dehydration, the infected cells will be removed
What is cystic fibrosis? What causes it? Who does it affect and why this group?
A complex inherited disorder caused by a mutation if the CFTR channel When CFTR does not open when signalled by cAMP Affects children and young adults because people with this condition don’t live into adulthood typically (median age is 38yrs old)
What is cystic fibrosis’s inheritance?
Autosomal recessive
How are heterozygous individuals for cystic fibrosis affected?
They are not, no symptoms but are carriers
What is the frequency of cystic fibrosis in different ethnic groups?
Northern Europeans have 1/2500, Asian and African populations less prevalent
What is the major form of mortality in patients with cystic fibrosis? What causes this?
Respiratory failure Lungs become damaged by mucus, bacterial infections, airway blockages and this reduces the area for gas exchange
How can cystic fibrosis affect the liver? What percentage of patients experience this?
Plugging of small bile ducts impede digestion and disrupts liver function 5%
How can cystic fibrosis affect the pancreas? What percentage of patients experience this?
Occlusion (e.g. blocking) of ducts prevent pancreas from delivering critical digestive enzymes to the bowel, causes pancreas to break down as digestive enzymes remain inside, can also cause diabetes in some circumstances (not 85%) 85%
How can cystic fibrosis affect the small intestine? Who and what percentage of patients experience this?
Obstruction of the gut by thick stools can lead to surgery 10% of new borns
How can cystic fibrosis affect the reproductive tract in males? What percentage of patients experience this?
Absence of fine ducts such as the vas deferent makes males infertile as they cannot produce seminal fluid for ejaculation 95%
How can cystic fibrosis affect the reproductive traction females?
A dense plug of mucus blocks sperm from entering the uterus (occasionally)
How can cystic fibrosis affect the skin? What percentage of patients experience this?
Malfunctioning of sweat glands causes perspiration to contain excessive NaCl (salt) 100% (is key characteristic of cystic fibrosis)
What is the common theme of cystic fibrosis in terms of the part of the organs being affected?
Epithelial tissue
What are some clinical management strategies of cystic fibrosis?
Chest percussion, antibiotics, pancreatic enzyme replacement, attention to nutritional status
What do chest percussions do to help alleviate symptoms of cystic fibrosis?
Helps dislodge mucus buildup in the lung tissue reducing the bacteria that can accumulate in the lungs
Why do CF patients take pancreatic enzyme replacement treatment?
To replace the enzymes that are not being produced anymore by the degraded pancreas
How is the CFTR channel controlled?
ATP needs to be hydrolysed in order for the ball and chain (regulatory domain) to open up the pore
What is unique about CFTR from all other ion channels?
It is the only one which uses ATP to open up the ion channel
Explain the process of opening the CFTR channel
cAMP is activated by G protein signal which then activates Protein kinase A which goes onto phosphorylate the regulatory domain, once the channel is phosphorylated ATP can bind to the nucleotide binding domain which open up the pore to allow free flow of Cl-
Label the diagram, what is this showing?
Shows a Cystic Fibrosis Conductance Regulator protein
What is coating the surface of the lungs?
A thin wet mucus layer
What is the purpose of the mucus coating on the lungs?
Allows for gas exchange and traps inhaled particles allowing cilia to push mucus up to the throat for removal (keeps the airway clear)
What happens to the lining of the lungs in a patient with CF?
The mucus layer becomes thick and difficult to remove resulting in a dry lung surface
How is the mucus layer lining the lungs maintained? What happens when it is not maintained?
There is a constant absorption and secretion action happening on the epithelial cells of the lungs on a healthy patient with Cl- pumped into the lumen creating secretion and Na+ pumped out of the lumen creation absorption When not regulated there can be too little secretion (dry lungs) or too much (drowning)
What happens to the ion pores on the epithelial tissue of the lungs in cystic fibrosis? How does this affect water movement?
Cl- channel (CFTR) become defective resulting in less/no Cl- and H2O secretion Na+ channel becomes overstimulated resulting in excessive Na+ and H2O absorption (not fully understood how they are linked FYI)
What develops on the lungs surface due to the lack of a mucus layer on the lungs? How does this affect the lung tissue? How does this affect respiration?
Bacteria, immune cells and DNA Immune cells are attracted to bacteria which inadvertently damage healthy tissue rupturing cells and releasing DNA, all increasing the stickiness/thickness of mucus continuing cycle Less surface for gas exchange to occur
What is the pathway of lung tissue damage due to the CFTR gene defect?
CFTR gene defect –> defective ion transport –> airway surface liquid depletion –> defective mucocillary clearance –> mucus obstruction/infection/inflammation
People with CF have what kind of sweat?
Very salty sweat
What are the stages of sweat formation?
1-A primary isotonic secretion of fluid by acinar cells 2-A secondary reabsorption of NaCl to produce a hypotonic solution (e.g. sweat)
For people with CF, which stage doesn’t work?
The secondary reabsorption of NaCl
What is the relative concentration of solutes in salt for a normal person compared with interstitial fluid? What kind of solution does this make it?
It has a lower concatenation than interstitial fluid Makes it hypotonic (low solute/high water conc)
Label the diagram. What is happening in this diagram?
Sweat formation
What do the acinar cells secrete? What classification of junction does it have?
An isotonic solution Leaky epithelium
What do the duct cells do?
Reabsorb the Na+ and Cl-
Why is water not reabsorbed during sweat formation as the ions move back into the cells?
The duct cells don’t have aquaporins and are electrically tight so no water moves back
What are the two pathways which can stimulate sweat production?
Parasympathetic and sympathetic nervous system
How do the parasympathetic and sympathetic nervous system stimulate sweat production differently?
Parasympathetic stimulation uses a ClCa protein channel which is stimulate by a Ca2+ messenger Sympathetic stimulation uses CFTR which is stimulated by cAMP
How do H2O and Na+ move from the interstitial fluid into the sweat duct?
Move via paracellular transport to maintain electroneutrality and osmolarity equilibrium
How does the Cl- get into the acinar cells for sweat formation? How is this different to other ways of moving Cl-?
Uses a NaK2Cl symporter It is the same in all epithelial cells
What process allows Na+ and Cl- to be reabsorbed by the duct cells in sweat formation? How do they get into the interstitial fluid?
They both move down their electrochemical gradient into the cell Na+ must be actively transported into interstitial fluid, Cl- continues down electrochemical gradient
What channels/transporters do Na+ and Cl- move through to get into the duct cells and then back into the interstitial fluid?
Na+ uses a ENaC protein channel to get into cell then is pumped out using Na/K pump Cl- uses CFTR to passively diffuse through cell and into interstitial fluid
Why can Cl- passively diffuse into the interstitial fluid from the duct?
There are no mechanisms transporting Cl- into the duct cells so there is a higher concentration of Cl- in the duct than cell and the duct cells are depolarised (e.g. have no charge on them). This allows Cl- to move down its concentration gradient into the cell *****why does Cl- move into interstitial fluid by diffusion but not Na+??? –Piazza @1134*****
Why do people with CF have salty sweat? consider the secretion and reabsorption mechanisms of sweat formation.
CFTR is non-functional therefore the Cl- is pumped out of acinar cells using parasympathetic systems (via Ca2+ signalling). During reabsorption however only CFTR channels are available so Cl- cannot travel down its electrochemical gradient. Na+ doesn’t move down its electrochemical gradient into the cell either in order to maintain electroneutrality resulting in sweat being secreted as an isotonic solution (e.g. salty) instead of hypotonic (normal sweat)
