Lecture 4 - CF and Small molecules 1

Question 1

CFTR is made up of…

Answer 1

12 TMDS

Question 2

CFTR is divided…

Answer 2

into two groups of 6 TMDs

Question 3

CFTR regulatory domain location and function

Answer 3

between the two subgroups and is where CFTR is phosphorylated by PKA

Question 4

NBD1 and 2 are…

Answer 4

important for gating

Question 5

what is the most common mutation and in what %?

Answer 5

F508del in 70-90% patients

Question 6

CFTR class I

Answer 6

unstable mRNA, degraded before protein synthesis so no CFTR produced

Question 7

CFTR class II

Answer 7

CFTR is made but does not reach the membrane due to misfiling leading to degradation

Question 8

CFTR class II example

Answer 8

F508del

Question 9

CFTR class III

Answer 9

CFTR enters membrane but PKA-mediated phosphorylation does not occur/channel does not respond to it. Decreased open probability

Question 10

CFTR class IV

Answer 10

CFTR in membrane but it does not open as effectively - conduction

Question 11

CFTR class V

Answer 11

mRNA partial reduction, so protein is made but there is less in the membrane

Question 12

CFTR class VI

Answer 12

high turnover of CFTR, enters the membrane but amount of time in membrane is reduced

Question 13

Sweat chloride diagnostic level

Answer 13

60mmolL-1

Question 14

Severe mutations and symptoms

Answer 14

I=III, higher sweat chloride levels with pancreatic insufficiency

Question 15

Carriers have…

Answer 15

50% normal CFTR levels

Question 16

How much normal functioning CFTR is required for normal function?

Answer 16

15% hypothesised

Question 17

ENaC and CFTR in the upper airway model

Answer 17

CFTR regulates ENaC

when one is open the other is closed

Question 18

CF and upper airway model

Answer 18

less CFTR function, so more ENaC function than normal

enhanced sodium reabsorption results in exacerbation of loss of fluid

Question 19

Upper airway model basolateral membrane proteins

Answer 19

Na+/K+ATPase
NKCC2
K+ channel

Question 20

Alveolar model CFTR and ENaC

Answer 20

both absorbing no secreting

Question 21

Alveolar model basolateral membrane proteins

Answer 21

K+/Na+ATPase
Cl-/K+ co-transporter
K+ channel

Question 22

Distal sweat gland model CFTR and ENaC

Answer 22

CFTR drives chloride reabsorption

CFTR activated ENaC

Question 23

Distal sweat gland and CFTR

Answer 23

CFTR is non-functional, no Cl- reabsorption

Loss of EnaC function

Question 24

Distal sweat gland model basolateral membrane proteins

Answer 24

Na+/K+ATPase, CFTR and K+ channel

Question 25

Kalydeco

Answer 25

Ivacaftor

G551D mutation potentiator

Question 26

Orkambi

Answer 26

Ivacaftor/Lumacaftor

potentiator and corrector for F508del homozygotes

Question 27

Symkevi

Answer 27

Ivacaftor/Tezacaftor

potentiator and corrector for F508del homo/heterozygotes

Question 28

Trifakta

Answer 28

Elezacaftor/ivacaftor and Tezacaftor

2 correctors and a potentiator for F508del homo/heterozygotes

Question 29

Forskolin

Answer 29

stimulates CFTR showing massive Isc increase

Question 30

G551D and CFTR

Answer 30

decreased increase in CFTR Isc

Question 31

G551D and Ivacaftor

Answer 31

increases ISC which potentiates CFTR function and enhances MT function to 40% normal WT function
massive Po increase

Question 32

G551D, Ivacaftor and ASL

Answer 32

height drops with CFTR and increased with Ivacaftor

Cilliary beat frequency also increases

Question 33

Ivacaftor clinical trials show

Answer 33

improvement of FEV1, decreased events and sweat chloride and improve nasal potential difference

Question 34

Isoprotenerol

Answer 34

used to measure nasal passage
B-receptor agonist
activates CFTR via cAMP