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PSC2002 > PSC2002/L06 NaCl and NaHCO3 secretion > Flashcards

PSC2002/L06 NaCl and NaHCO3 secretion Flashcards

1
Q

Describe the mechanism of NaCl secretion by epithelial cells of the GI tract, exocrine glands and conducting airways. (3)

Wrong

A

Movement of Na+ driven by paracellular Cl- transport
Cl- inside cell relatively low 10-20mM (outside 120mM)
Secondary active transport of Cl- coupled to Na+ facilitated diffusion

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2
Q

Give the 2 types of Cl- channels in epithelial cells.

A

CFTR
Ca2+-activated Cl- channel (CaCC)

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3
Q

Give the 5 main domains of the CFTR.

A

MSD1&2 - pore of channel
NBD1&2 - bind ATP
RD - site of phosphorylation

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4
Q

Why is the CTFR a different kind of ABC transporter to the rest?

A

Only ABC transporter that is an ion channel not an active pump

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5
Q

Describe the molecular mechanism of CTFR gating. (4)

A

PKA phosphorylation of RD induces ATP binding and dimerisation of NBDs
Conformational change in NBDs transmitted to MSDs leading to pore opening
ATP hydrolysed (site 2) and pore closes
Dephosphorylation by protein phosphatases closes channel

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6
Q

What will occur if another ATP binds during the pore closing stage of CFTR gating?

A

Channel re-opens as long as RD is phosphorylated

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7
Q

What 2 criteria need to be met for CFTR to open?

A

PKA phosphorylation
ATP binding

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8
Q

Describe the experimental evidence that CFTR requires both PKA phosphorylation and ATP binding to open.

A

Inside-out patch of membrane taken
Both ATP binding and PKA phosphorylation controlled and introduced and separate times
Voltage only produced whilst both present

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9
Q

Where are calcium-activated Cl- channels (CaCC) present? (4)

A

In apical membrane of most epithelial cells that express CFTR
Apart from intestinal cells
Apical membrane of gland secretory acinar cells (no CFTR)
Some endocrine cells, smooth and skeletal muscle and neurones

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10
Q

How are CaCC activated? (2)

A

Rise in cytosolic Ca2+
Calmodulin (CaM) & CAM dependent kinase (CaMK) but not essential for activity

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11
Q

Give 2 CaCCs from the TMEM16 family.

A

TMEM16A
TMEM16B

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12
Q

Describe the structure of TMEM16A.

A

10 TMDs - pore region 6-9
Recent crystal structures indicate that a ‘functional channel’ is a dimer

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13
Q

What triggers opening of TMEM16A? (3)

A

Ca2+ binds to glutamate residues in 1/2 a-helices of intracellular loop 3 (ICL3)
a-helices move apart
Pore opens

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14
Q

When does TMEM16A close?

A

When cytosolic Ca2+ reduces back to resting levels (~100nm)

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15
Q

Give the 2 main mechanisms of HCO3- transport.

A

Directly through Cl- channel
Indirectly via coupling Cl- channel with apical Cl-/HCO3- exchanger

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16
Q

What is the result of coupling a Cl- channel to an apical Cl-/HCO3- anion exchanger (AE)?

A

Net epithelial NaHCO3 secretion

17
Q

Which family of transporters do the AEs belong to?

A

SLC26 (solute carrier 26)

18
Q

What is a feature of many epithelia that secrete HCO3-?

A

Have Na+-dependent HCO3- transporters (NBCs) on basolateral membrane that supplies cytosolic HCO3- for exchanger
SLC4 family

19
Q

What is the activity of SLC26A AEs regulated by?

A

PKA phosphorylation of CFTR switches on AE activity for SLC26, A3, A6 and A9
Requires physical interaction of 2 proteins aided by ‘scaffold’ protein, CAP70 and CFTR RD phosphorylation

20
Q

What may occur to SLC26A AEs if CFTR is dysfunctional? (2)

A

AE inhibited
Reduced net HCO3- and fluid secretion

21
Q

Where in the body is HCO3- secretion regulated by CFTR? (3)

A

Small intestine
Biliary tract
Exocrine pancreas
Airways
Female and male reproductive tracts

22
Q

What is the function of acinar cells (AC) in the exocrine pancreas?

A

Secrete digestive enzymes and low volume, NaCl-rich fluid into ducts using TMEM16A channels

23
Q

What is the function of duct cells in the exocrine pancreas? (2)

A

Transport digestive enzymes to SI
Produce high volume, NaHCO3-rich secretion suing both CFT and SLC26A6

24
Q

What is fluid secretion in the GI tract driven by?

A

Both NaCl and NaHCO3 secretion with FCTR dominant anion channel

25
Q

What is fluid absorption in the GI tract driven by?

A

Multiple absorptive mechanisms depending on site in GI tract
Secondary to sodium absorption

26
Q

How much fluid is…
a) contained in the average 70kg person?
b) secreted by the GI tract per day?
c) lost in faeces per day?

A

a) 42L
b) 7L
c) 100ml

27
Q

What is the result of failure in fluid absorption? (2)

A

Rapid dehydration
Electrolyte imbalance
Death in severe cases

28
Q

Describe ENaC-mediated fluid absorption.

A

Only occurs in the colon

29
Q

Describe the role of sodium-linked absorptive ion transporters.

A

In apical membrane
Mutations in DRA cause Cl- losing diarrhoea

30
Q

Describe the role of nutrient absorptive transporters.

A

In apical membrane

31
Q

Describe secretory diarrhoeas and how they are caused by dysregulation of fluid homeostasis.

A

Most due to dysregulation of cell signalling
Leading cause of death in children under 5
Can mostly be prevented through safe water-drinking and adequate sanitation and hygiene

32
Q

Describe how secretory diarrhoeas are caused by infection with vibrio cholerae.

A

Inhibits NaCl & fluid absorption from villi
Stimulates CFTR-mediated Cl-/HCO3- & fluid absorption from crypts

33
Q

How can oral rehydration therapy be used to treat fluid dysregulation?

A

Isosmolar (or hypo-osmolar) salt solution containing NaCl, NaCitrate, KCl and Glucose
Recommended to use starch over glucose - prolongs ORT
Rice milk and coconut alternatives
Rapid reabsorption by utilising nutrient absorptive transporters

34
Q

How does cholera toxin lead to dehydration? (6)

A

Causes ADP-ribosylation of G-protein (a(s)) that blocks GTP hydrolysis by this subunit
AC becomes permanently active
Lots of cAMP produced
Uncontrolled overstimulation of CFTR
Inhibition of electroneutral NaCl absorption
Excessive salt & water loss into intestinal lumen

35
Q

Give a treatment option for cholera toxin.

A

Oral rehydration therapy
Intravenous fluid

PSC2002 (5 decks)

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