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BMS 346- Epithelial physiology in health and disease > Lecture 4 - CFTR and Salt secretion > Flashcards

Lecture 4 - CFTR and Salt secretion Flashcards

1
Q

Discuss first observations CL- secretion

A

Learning Objective

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2
Q

Discuss the function of CFTR

A

CFTR- Chloride channel in the epithelial membrane required for cl- secretion

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3
Q

Discuss the defects in transport in CF

A

Learning Objective

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4
Q

Evaluate the evidence for a defect in CF in the colon

A

Learning Objective

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5
Q

Cystic Fibrosis

A
  • Most common lethal genetic disease in
  • Caucasians
  • Exocrine pancreatic insufficiency
  • Increased sweat [Cl-]
  • Male infertility 95%- critical for normal dev of reproductive system
  • Airway disease
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6
Q

What is the test for CF in babies?

A

Guthry Test

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7
Q

Guthry Test

A
  • foot prick in infants
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8
Q

Female infertility in CF patients

A

5%

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9
Q

Give examples of epithelia capable of secreting NaCl rich fluid

A 
•	exocrine gland acini   
• sweat gland coil
•small intestine		 • upper airway
•choroid plexus
-Shark rectal gland
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10
Q

What is an important model tissue for CF and why ??

A

Shark rectal gland

  • lasts for hours
  • large amount of secretion and very robust for experiments
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11
Q

First experiment- manipulation of Cl secretion using a pharmacological approach

A

change the ionic species present in the extracellular fluid compartment and see impact on the secretion
- Shark rectal gland
-oubain to block Na/K pump
-Barium to block K channel
- added one or the other to basolateral surface and measured Cl secretion
RESULTS
Na/K atpases blocked cl secretion to nothing – critical for normal cl secretion > sets up driving forces
- Block K using Barium membrane potential closer to 0

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12
Q

K channel

A

Maintains negative membrane potential

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13
Q

Na/K atp ase

A

maintains low intracellular sodium

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14
Q

Chloride Transport inhibitors

A
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15
Q

Extensions of experiment 1 - Shark Rectal Gland

A
  • remove NA block CL

- remove K blocks CL

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16
Q

important Driving force

A

na/k and K channels set up driving force for NA influx across the membrane
block K –

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17
Q

Describe the proposed model from experiment 1

A

On basolateral side-
Na/K atpase
K channel
Nkcc1

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18
Q

Block Na/K Atpase

A
  • Intracellular sodium goes up so driving force goes down and therefore doesnt function as well
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19
Q

Block K channel

A

Depolarise membrane potential and reduce the driving force for Na influx and therefore inhibit function of Nkcc1

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20
Q

Furosemide

A

Directly inhibits Nkcc1

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21
Q

How to Cl ions get in ?

A

Chloride Ions get in through Nkcc1 but Nkcc1 is dependent K channel funciton

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22
Q

What happens to Cl- ions across the membrane ?

A

Cl- ions are recycled

23
Q

Cl calculations

A

Compare the nernst with the measured membrane potential
or if membrane purely selective for Cl
you can rearrange cl concentration if you dont have either the intracellular value or the extracellular value
-Calculate CL in if CL passively distributed across the - no active component

24
Q

Issule with Cl calculation Data

A
  • Active component in the suggested model
  • data produced not expected - higher so shows there must be an active component involved and accumulating cl in the cell therefore above electrochemical equilibrium
  • supports model from experiment 1
25
17 -28 mM in the cell suggests what
No active component in the cell
26
If ion above its electrochemical equilibrium
to get it out of the cell all you need is to open a channel on apical membrane - driving force now for Cl- to leave the cell
27
Completed model - 4 components
Basolateral side - Na/K atpase K channel NKcc1 ``` Apical side- CL channel (cAMP activated) ```
28
Increase in cAMP
Cl channel increased activation > more CL secretion | cAMP stimulated the conductance and overall secretion
29
Furosemide
Brings Ecl to equilibrium
30
Microelectrodes in complete model
- in the apical membrane Pcl is high | - apical membrane potential moves the nernst potential for chloride
31
Cystic Fibrosis gene product
CFTR- | Cl- channel in the apical membrane
32
CFTR Structure :
- 12 Transmembrame domains - 2 nucleotide binding domains – seq of aa with binding sites for nucleotides - R domain- regulation domain – phosphorylation consensus sequences by PKA
33
CFTR mutations :
-Lots of mutations in NBD1 and NBD2 – critical for normal functions F508 mutations in NBD! – very common 70%
34
Mutations classes
- Class IV Conduction - Class III Regulation (protein made but reg not normal) - Class VI High turnover CFTR ( time at cell mem red compared to normal) - Class II Trafficking - Class I Null production (unstable mRNA) - Class V Partial reduction mRNA
35
F508
misfolded trafficking mutant | Only 15-20% of normal level in upper airways for normal function
36
Variation within mutations-
Drugs target various classes Mutation determines the severity But can have a range of symptoms with the same mutation – compliance specific and genetic background gives rise to variation
37
What is a key measure for Cf function/ class?
Sweat chloride Class 1-3 mutations – 100 mM sweat most severe 60 mm clinical cut of point
38
Carriers
50% normal Cftr
39
Rat colonic crypt cells -
- lower 2/3rd cl secreting - content of crypt in contact with the lumen of colon -what ever moves into lumen lost in defecation - CFTR channels on apical membrane - more Cl secreted more water you secrete in faeces - Anything that disrupt Cl secretion reduces the secretion in the colon - More active K channels are the bigger driving force for CL secretion - Na secreted paracellularly - PGE2 stimulated by binding of prostaglandins – activations stimulates cl secretion - Activate ACh receptor stimulate cl secretion
40
Basolateral - | Apical-
Blood - BB | Airway- AA
41
Ach
increase in Ach binds to AchR induces increase in intracellular Ca activates apical and basolateral k channels - stimulate Cl secretion
42
PGE2
- PGE2 Receptor stimulated by the binding of Prostaglandin- GPCR - leads to increase in cAMp which stimulates PKA which stimulates CFTR - Stimulate CL secretion
43
Carbacol
Ach R agonist | effect > Rise in intracellular Ca
44
Indomethacin
inhibits PG production | Effect> decrease in cAMP
45
IBMX
inhibits phosphodiesterases which usually break down cAMP | Effect> increase in cAMP
46
Forskolin
Activation of adenylate cyclase - leads to production of cAMP Effect- increase cAMp
47
Short circuit current exp in human colonic mucosa
Amiloride blocks ENAc so its not contaminated -Carbachol stimulates k channels but cl zero so no cl secretion – driving force there but cl channels not open – needs cAmp to activate cl channels as well
48
CF colon -
Blockages - dont secrete chloride Meconium ileus ~10% newborns - surgery required
49
CFTR and ENac
CFTR inhibits ENac in UPPER AIRWAY When one is functioning the other isn’t When CFTR mutated ENac enhanced enhanced absorption of sodium and enhanced absorption of water - makes symptoms worse
50
Alveolar model
Basolateral membrane - K/Cl co transport protein driven by k gradient - move K an cl out - CL inside alveolar cell belo2 equilibrium - so CFTR in apical open you get Cl absorption - IIN ALVEOLAR ENac and CFTR work together
51
Alveolar oedema
Can be a symptom of CF | - critical because alveoli site of gas enhance inhibits ability to extract oxygen
52
Distal sweat glands
too much Na and CL CF salty sweat due to problem with NaCl reabsorption - secrete NaCL from one set of cells and the fluids move down and reabsorbed again but if process doesnt work properly you lose NaCl in sweat
53
CFTR in distal sweat glands
activates ENac in the distal sweat gland

BMS 346- Epithelial physiology in health and disease (13 decks)

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