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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
Q

17 -28 mM in the cell suggests what

A

No active component in the cell

26
Q

If ion above its electrochemical equilibrium

A

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
Q

Completed model - 4 components

A

Basolateral side -
Na/K atpase
K channel
NKcc1

Apical side- 
CL channel (cAMP activated)
28
Q

Increase in cAMP

A

Cl channel increased activation > more CL secretion

cAMP stimulated the conductance and overall secretion

29
Q

Furosemide

A

Brings Ecl to equilibrium

30
Q

Microelectrodes in complete model

A
  • in the apical membrane Pcl is high

- apical membrane potential moves the nernst potential for chloride

31
Q

Cystic Fibrosis gene product

A

CFTR-

Cl- channel in the apical membrane

32
Q

CFTR Structure :

A
  • 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
Q

CFTR mutations :

A

-Lots of mutations in NBD1 and NBD2 – critical for normal functions
F508 mutations in NBD! – very common 70%

34
Q

Mutations classes

A
  • 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
Q

F508

A

misfolded trafficking mutant

Only 15-20% of normal level in upper airways for normal function

36
Q

Variation within mutations-

A

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
Q

What is a key measure for Cf function/ class?

A

Sweat chloride
Class 1-3 mutations – 100 mM sweat most severe
60 mm clinical cut of point

38
Q

Carriers

A

50% normal Cftr

39
Q

Rat colonic crypt cells -

A
  • 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
Q

Basolateral -

Apical-

A

Blood - BB

Airway- AA

41
Q

Ach

A

increase in Ach binds to AchR induces increase in intracellular Ca activates apical and basolateral k channels
- stimulate Cl secretion

42
Q

PGE2

A
  • PGE2 Receptor stimulated by the binding of Prostaglandin- GPCR - leads to increase in cAMp which stimulates PKA which stimulates CFTR
  • Stimulate CL secretion
43
Q

Carbacol

A

Ach R agonist

effect > Rise in intracellular Ca

44
Q

Indomethacin

A

inhibits PG production

Effect> decrease in cAMP

45
Q

IBMX

A

inhibits phosphodiesterases which usually break down cAMP

Effect> increase in cAMP

46
Q

Forskolin

A

Activation of adenylate cyclase - leads to production of cAMP
Effect- increase cAMp

47
Q

Short circuit current exp in human colonic mucosa

A

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
Q

CF colon -

A

Blockages - dont secrete chloride
Meconium ileus
~10% newborns
- surgery required

49
Q

CFTR and ENac

A

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
Q

Alveolar model

A

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
Q

Alveolar oedema

A

Can be a symptom of CF

- critical because alveoli site of gas enhance inhibits ability to extract oxygen

52
Q

Distal sweat glands

A

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
Q

CFTR in distal sweat glands

A

activates ENac in the distal sweat gland

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

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