Epithelial Chloride Channel 4 Flashcards

1
Q

First CFTR KO mouse

A

1992 - Beverly Koller

3 groups

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2
Q

Gabriel et al 1993

A

CFTR and ORCCs distinct proteins in regulatory relationship

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3
Q

Gabriel 1993 findings - ORCCs and CFTR

A

KO mice lacking CF gene express ORCCs
PKA only activates ORCCS in CFTR expressing cells
CFTR involved in regulating ORCCs by PKA

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4
Q

1995 Jovov

A

CFTR and ORCCs

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5
Q

Explain Jovov 1995

A

CFTR and ORCC immunopurified from bovine trachea
planar lipid bilayers
nonfunctional mutant –> functional mutant
CFTR needed for OCC activation by ATP and PKA

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6
Q

Smith 1996

A

airway surface liquid bacteriacidal

pseudomonas aeruginosa bacteria killed in normal but thrive in CF airway

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7
Q

epithelial human b defensins

A

1 and 2

important natural bacteriacidal agents

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8
Q

HBD1 and 2 - Singh et al 1998 findings

A

present in normal and CF
HBD activity dependent on ionic strength of medium
If NaCl high then reduction in killing

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9
Q

singh et al 1998 lysosymes

A

in saliva - also affected by salts but not by non-ionic osmolytes
charge important

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10
Q

which HBD particularly affected by NaCl conc?

A

1

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11
Q

thiocyanate

A

sodium iodide transporter in basolateral membrane
exit via CFTR
important in bacteriacidal action

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12
Q

Conner et al 2006

A

thiocyanate (-ve)
duox enzyme thiocyanate –> hypothiocyanate
reduced SCN transport by CFTR impairs lypoxygenase mediated bacteriacidal action

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13
Q

thiocyanate or hypothiocyanate bacteriacidal?

A

hypothiocyanate

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14
Q

Type 1 CFTR defect and therapy

A

protein production
gentamicin - suppress premature termination of transcription
read through compounds

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15
Q

Type 2 CFTR defect and therapy

A

Processing

CFTR chaperones - stabilise protein structure/promote folding - expression in apical membrane

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16
Q

Type 3 CFTR defect and therapy

A

Regulation
CFTR activators : flavinoids, alkylxanthines prevent cAMP breakdown
MBP derivatives

17
Q

what kind of defect is dF505?

A

type 2 - processing

18
Q

type 4 defect and therapy

A

conduction

CFTR potentiators: VX 770

19
Q

What is vx770?

20
Q

MPB-07 - Becq 1999

A

measure Isc over time
apply cpt-cAMP increase in secretion
glibenclamide inhibits CFTR bring current down - normal
MPB-07 = increase in current, similar to levels with cAMP - activate CFTR

21
Q

MPB-07 Iodine channels CFTR

A

iodine efflux only with MPB-07 not IBMX

getting deltaF508 to the membrane - chaperone aswell as an activator

22
Q

Pedemonte 2005

A

amiloride then FSK - not much in deltaF508

lower temperature FSK has more effect

23
Q

amiloride

A

KO sodium channels Enac

24
Q

FSK

A

activates adenylate cyclase then cAMP

25
Van Groor et al 2009
rat thyroid cells FSK not much effect VX770 big effect on Isc - activity through CFTR
26
Van Groor et al 2009 dF508 and G551D
FSK does little VX770 substantial increase in current in human bronchial epithelium G551D at membrane, better even though not at membrane
27
Orkambi
``` Ivacaftor - VX770 Lumacaftor - VX809 licensed UK 2015 deltaF508 CFTR +/+ >£100, 000/year approved NHS in 2019 ```
28
lumacaftor
CFTR chaperone and corrector
29
CF airway and ENaC
increased sodium conductance in apical membrane CFTR inhibits Enac in airway in CF --> airway surface dehydration water follows
30
CFTR and Enac in sweat duct
CFTR activate Enac in sweat duct | absence of CFTR in CF - salty sweat
31
last 4 amino acids at c terminus of CFTR
aspartic acid, threonine, arginine, leucine
32
what do 4 amino acids at c terminus of CFTR bind?
PDZ proteins
33
PDZ proteins
PSD-95, zo-1, Dlg | apical localisation of CFTR?