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Cell Membrane > Lecture 25: Chloride Secretion > Flashcards

Lecture 25: Chloride Secretion Flashcards

1
Q

How many steps is in this process?

A

2

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2
Q

How is chloride accumulated in the cell, above its electrochemical equilibrium?

A

By a cotransporters located in the Basolateral membrane

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3
Q

What does the accumulation of chloride enable?

A

It enables chloride to leave the cell via a channel located in the apical membrane

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4
Q

Why does sodium move via the paracellular pathway?

A

To preserve electroneutrality

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5
Q

Where does the chloride secretion move chloride from?

A

Blood to lumen (opposite of absorption)

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6
Q

What are the 6 key features of chloride secretion across an epithelial cell?

A
  1. Tight junctions
  2. Sodium/potassium pump
  3. NaKCl cosymporter accumulates chloride above its electrochemical gradient
  4. Cl leaves the cell by passive diffusion through the apical membrane
  5. Na exits the Basolateral membrane and K via a channel (diffusion)
  6. Paracellular transport of Na and h2o
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7
Q

What is step 1 of chloride secretion?

A

Tight junctions divide cells into apical and basalateral membrane domains

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8
Q

What is step 2 of chloride secretion?

A

The Na/K pump sets up the ion gradients (ATP hydrolysis)

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9
Q

Step 3 of chloride secretion?

A

The Na/K/Cl cosymporter uses the energy from the Na gradient to accumulate chloride above its electrochemical gradient. (Entry step for chloride). Transports 4 ions. Example of secondary active transport. Is electrogenic; (two positive, two negative ions)

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10
Q

What does raising the level of chloride above its electrochemical equilibrium inside the cell mean?

A

Chloride will want to leave the cell (but can’t get across hydrophobic bilayer).

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11
Q

Step 4 of chloride secretion?

A

Cl leaves the cell by passive diffusion through an ion channel (in apical membrane) (so, transport from blood to lumen; an active step in the Basolateral membrane and a passive step in the apical membrane)

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12
Q

Step 5 of chloride secretion?

A

Sodium is moved back across the membrane by the Na/kATPase. (Sodium that leaks in via the NaKCl cosymporter is pumped out).
K diffuses down its electrochemical gradient via a k channel in the Basolateral membrane

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13
Q

Step 6 of chloride secretion?

A

The transport of Cl across the epithelium induces paracellular Na and water fluxes

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14
Q

Why is the removal of potassium important?

A

Because its exit leaves behind a negative charge (increasing or maintaining the resting membrane potential, making it more negative, so chloride wants to leave cell-therefore enhances electrochemical gradient for chloride to move out if the cell)

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15
Q

What does the movement of chloride into the lumen do to the lumen?

A

It makes the lumen negative

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16
Q

What happens if the lumen is negative?

A

It attracts positive ions which attracts water

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17
Q

So what does chloride secretion secrete in total?

A

Sodium chloride and water (as chloride attracts sodium and water via paracellular transport)

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18
Q

What is the osmolarity of the secretes chloride solution?

A

The same as the osmolarity of the blood

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19
Q

What tonicity of fluid have you secreted via chloride secretion?

A

An isotonic solution

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20
Q

What happens in chloride solution (in regards to volume)

A

You e moved the volume of fluid in the blood across the epithelial cell into the lumen

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21
Q

What can be in the solution secreted into the lumen?

A

Saliva and enzymes (which in small intestine can facilitate the process of digestion)

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22
Q

Why does chloride secretion occur?

A

Movement of chloride across the cell

Leaky tight junction allowing Na/h2o to cross

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23
Q

How are the tight junctions in chloride secretion different to in glucose secretion?

A

It’s more permeable to sodium than chloride (so a change in molecular permeability of tight junctions)

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24
Q

Why do you need to control chloride secretion?

A

If you don’t, you will pump your body dry of all your salts and waters (therefore, become dehydrated)

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25
What happens if the chloride channel is continuously open?
Chloride will keep moving out of the cell (and therefore water and sodium too); as its a channel, millions of chloride ions can move through per second)
26
Although Cl is accumulated in the cell above its electrochemical equilibrium, why can it not leave the cell?
Because it can only leave the cell when the Cl channel is open
27
Is the Cl channel strictly regulated?
Yes, it is gated
28
What is the rate limiting step of Cl secretion?
The opening/closing of the chloride channel (for example, bread shop analogy- neurotransmitters cause the Cl channel to open as saliva is generated to start digestion process)
29
What is the official name of the chloride channel?
The cystic fibrosis transmembrane conductance regulator (CFTR)
30
Does everyone have the CFTR gene?
Yes, normally it's fine, but in those with cystic fibrosis the gene is mutated (which relates to chloride secretion)
31
What happens in normal people if you overstimulate the CFTR gene?
You get secretory diarrhoea
32
What happens to the CFTR gene if you have cystic fibrosis?
The CFTR is mutated, dysfunctional and essentially blocked
33
What does excessive stimulation of secretory cells in the crypts of small intestines and the colon cause?
Secretory diarrhoea
34
Two types of causes for secretory diarrhoea?
1. Due to abnormally high concentrations of endogenous secretagogues 2. Secretion of enterotoxins from bacteria
35
How does abnormally high concentrations of endogenous secretagogues cause secretory diarrhoea?
The secretagogues, produced by tumours or inflammation can overstimulate chloride secretion
36
What are secretagogues?
A substance that promotes secretion
37
What types of bacteria causes secretory diarrhoea?
Vibrio cholerae, which secretes enterotoxins which open the chloride channel
38
How does enterotoxins from bacteria cause secretory diarrhoea?
It interferes with the signalling pathway; as enterotoxins irreversibly activate adenylate cyclase causing a maximal stimulation of CFTR which leads to a secretion that overwhelms the absorptive capacity of the colon (as its no longer gates, the colon can't reabsorb fast enough = diarrhoea)
39
What happens in normal chloride secretion?
Secretagogues bind to g-protein coupled receptor, activated adenylate cyclase, causes ATP to activate cAMP which causes Protein kinase A to activate CFTR (aka opens channel); when secretagogue isn't present, there is no pathway (like a switch)
40
What happens in cholera toxin chloride secretion?
Cholera toxin irreversibly activates adenylate cyclase causing the activation of CFTR (so, it can't be stopped); which causes mass dehydration (eg, an adult can lose 20L water)
41
What is the normal balance of fluid in the small intestine?
Villi have glucose absorption (pull in glucose, amino acid, water), crypt cells secrete the NaCl dilution for digestion along with enzymes to break down starch and amino acids
42
How much do you secrete/absorb each day?
Secrete about 9L fluid, reabsorb about 8.5L (about .5L excreted)
43
What happens in secretory diarrhoea?
Secretion overwhelms absorption (so you need to stimulate reabsorption)
44
How do you treat secretory diarrhoea?
With a drip or oral rehydration therapy (specifically for cholera)
45
What do infected cholera crypt cells do?
They migrate and turn into glucose reabsorption cells (change protein expression)
46
How long does the life cycle of the crypt cells take?
5 days (so you need to keep someone hydrated for 5 days)
47
What is cystic fibrosis in functional terms?
What happens when you block the chloride channel
48
What is the disease cystic fibrosis?
A genetic disorder that affects children and young adults
49
How is cystic fibrosis inherited?
In an autosomal recessive fashion (Heterozygotes have no symptoms but are carriers) (The child of two carriers has a 1 in 4 chance of getting cystic fibrosis)
50
Does cystic fibrosis vary among ethnic groups?
Yes
51
What ethnic group has high cystic fibrosis rates?
Northern Europeans (about 1 in 2500 newborns have the disease, about 1 in 25 are carriers It's less common in other ethnic groups
52
Is cystic fibrosis the most lethal genetic disease?
Yes
53
When was the first comprehensive description of CF?
1938
54
When was the demonstration that excessive salt loss is associated with CF?
1953
55
When was the demonstration that epithelial cl- secretion is defective in CF?
1983
56
When was CF linked to long arm of chromosome 7?
1985
57
When was the linkage of cAMP pathway to CF?
1986
58
When did patch clamp studies show CF due to defective regulation of a Cl channel?
1987-1989
59
When was the CF gene cloned?
1989
60
When was the molecular physiology of CF channel regulation?
1990-1994
61
When was a gene therapy and a cure for CF hopeful?
1995
62
When were gene therapies specific for CFTR mutations?
21st century
63
What organs affected by cystic fibrosis?
Airways, liver, pancreas, small intestine, reproductive tract, sweat gland
64
What is the common theme between among the organs affected by cystic fibrosis?
The involvement of epithelial tissues (and is a disease of secretion in epithelial tissues)
65
What are most CF mortality cases caused by?
Respiratory failure
66
What is the median survival rate?
38 years
67
What happens to the airways in CF?
You get a mucous/infection in the lungs
68
What happens to the liver in CF?
Bile ducts get blocked
69
What happens in the pancreas in CF?
Pancreatitis; pancreas gets destroyed as its not secreting enough fluid
70
What happens to the small intestine in CF?
Bowel gets blocked
71
What happens to the reproductive tract in CF?
Males are infertile, as not producing enough speed to ejaculate
72
What happens to the sweat glands in CF?
The sweat is very salty even when the individual is not exerting themselves (this is also a type of early diagnosis)
73
What is the clinical management of CF?
- chest percussions to improve clearance of infected secretions - antibiotics to treat infections - pancreatic enzyme replacement - attention to nutritional status
74
How is CFTR regulated?
It's a Cl channel regulated by protein A kinase dependent phosphorylation of the R domain and binding of the ATP to the nucleotide binding domain (ATP causes channel to open, when it's hydrolysed to adp it closes)
75
What is the first stage of sweat formation in cystic fibrosis?
A primary isotonic secretion of fluid by acinar cells
76
What is the second stage of sweat formation in am cystic fibrosis?
A secondary reabsorption of NaCl to produce a hypotonic solution
77
What causes the salty swear in cf patients?
The failure of epithelial cells in the sweat glands to reabsorb NaCl
78
What are normal lung epithelial cells like?
Right amount of fluid. Particles stick to mucous A balance between secretion and absorption keeps lung surface moist but prevents build up Thin, wet mucous traps inhaled particles, allows cilia to push mucous up to throat for removal and keeps airways clear for breathing
79
What are lung epithelial cells in CF like?
- defective Cl channel prevents isotonic fluid secretion and enhances Na absorption to give a dry lung surface - mucous becomes difficult to remove, bacteria proliferates and attract immune cells, which can damage healthy tissue - DNA released from bacteria and lung cells add to stickiness. Airways become plugged and begin to deteriorate (less area got gas exchange)
80
What is the lung pathology sequence in CF?
1. Defective gene defect (hopes to change with gene therapy) 2. Defective ion transport (new therapies here) 3. Airways surface liquid depletion 4. Defective mucoclillary clearance 5. Mucous obstruction 6. Infection/inflammation cycle
81
What happens in normal duct cells?
The membrane potential is depolarised and Cl wants to enter the cell down electrochemical gradient, in CF patients CF is defective and ur accumulates in duct lumen producing salty sweat **check

Cell Membrane (6 decks)

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