Transport Proteins

Question 1

The Na+/K+ pump uses up how much of the cells ATP?

Answer 1

40%.

bonus: there are thousands of them on each cell.

Question 2

5 drug types that can bring on long QT

Answer 2

Class III antiarrhythmics, antibiotics, tricyclic antidepressants, cholesterol-lowering drugs, cancer meds.

Question 3

What happen over QRST?

Answer 3

The ventricles depolarise and contract

Question 4

What does the T-wave represent?

Answer 4

Ventricular repolarisation.

Question 5

What does a long QT interval indicate?

Answer 5

Some kind of abnormal after-depolarisation or re-entrant depolarisation.

Question 6

Recall - are myocardial cells Na-dependent or Ca-dependent?

Answer 6

Na-dependent.

Question 7

Why is tetanisation of skeletal muscle possible but not cardiac muscle?

Answer 7

The absolute refractory period of skeletal muscle is about 1-2ms compared to 50s for contraction (and another 50 for relaxation). So another excitation can occur before contraction is ceased.

In heart muscle the end of the absolute refractory period and contraction more or less coincide - until it starts relaxing, a new excitation isn’t possible.

Question 8

Which K+ blocker from PCOL2 is known for leading to Torsade-de-pointes?

Answer 8

amiodarone

Question 9

Which is phase 3 of the cardiac action potential?

Answer 9

The return from plateau to baseline.

Question 10

At the end of phase ___, Vm has returned to baseline (by definition).

Answer 10

phase 3

Question 11

EADs occur in __________.

Answer 11

Late phase 2 or phase 3.

Question 12

DADs occur in __________.

Answer 12

Phase 4 or late phase 3.

Question 13

Long QT syndrome is caused by a reduced repolarising (K+) current in types…

Answer 13

1,2 and 5,6

Question 14

LQTS1,2,5 and 6 are all caused by…

Answer 14

mutations in K+ channels, resulting in reductions in polarising current.

Question 15

LQTS3 is caused by…

Answer 15

mutation in the Na+ channel, causing late inactivation which acts as a source of late depolarising current.

Question 16

Which LQTS is caused by late the late inactivation depolarising currents?

Answer 16

LQTS3 i.e. the sodium channels close late.

Question 17

What is the mainstay treatment of congenital LQTS?

Answer 17

Implanted device i.e. pacemaker.

bonus: also a “cardioverter defibrillator”

Question 18

What symptoms of LQTS would be described as very “well, what was that then?”

Answer 18

Syncope from TdP.

It resolves spontaneously and the patient comes to usually feeling fine.

Question 19

Syncope can be fine or…

Answer 19

or the TdP escalates into ventricular fibrillation causing sudden death.

nb on terms: TdP is a ventricular arrhythmia that can deteriorate into v-fib.

Question 20

What is an obvious thing that can precipitate in irregular rhythms?

Answer 20

HR-increasing stuff, e.g. exercise or emotions.

Question 21

What form of exercise is especially bad in LQTS?

Answer 21

Swimming

Question 22

Why is sympathetic stimulation (“andrenergic states”) particularly bad in LQTS?

Answer 22

Because sympathetic stimulation works by increasing L-Ca+ channel activity.

Question 23

Which LQTS affects calcium channels?

Answer 23

LQTS 8

Question 24

LQTS 8 affects which channels?

Answer 24

calcium

Question 25

One more time: which drugs in particular set on LQTS?

Answer 25

Class III antiarrhythmics (K+ blockers).

Question 26

Which is the recessive LQTS? | My only friend at recess and lunch was my imaginary gerbil Lord Nelson.

Answer 26

Jervell, Lange-Nielson

Question 27

Which is the dominant LQTS? | Everybody Loves Raymond propogated male dominance, not winning any awards from me.

Answer 27

Romano-Ward

Question 28

Which is the recessive LQTS?

Answer 28

Jervell, Lange-Nielson

Question 29

Which is the dominant LQTS?

Answer 29

Romano-Ward

Question 30

How long is a long QT?

Answer 30

≥ 0.47.sec

Question 31

Is LQT3 due to early opening or late closing?

Answer 31

TRICK neither. I was confused by the contradictory language but as a whole, the mutant Na+ channels have a tendency to revert in and out of the open state for a prolonged period. As a population, this could be described as either "early activation" or "late inactivation" of the depolarising current. For the exam we'll call it late inactivation.

Question 32

CFTR is located on chromosome _.

Answer 32

CFRT: chromosome SEVEN. 7

Question 33

What is the incidence of LQTS?

Answer 33

1/5000

Question 34

What is the incidence of cystic fibrosis?

Answer 34

1/2500

Question 35

How many people carry the CF ∆F508 mutation?

Answer 35

1/25

Question 36

What's the most common mutation in CF?

Answer 36

Missing phenylalanine residue at position 508 (∆-F508 )

Question 37

What's a medal that CF holds?

Answer 37

Most common autosomal recessive disease in Australia.

Question 38

Name five organs affected by CF

Answer 38

Airways, intestines, pancreas, liver, reproductive tract

Question 39

Classes range in awfulness from no synthesis to decreased abundance. What are the classes?

Answer 39

``` I No synthesis II No maturation III Bad regulation IV Decreased conductance V Decreased abundance. ```

Question 40

What's class II CF?

Answer 40

No maturation

Question 41

What's Class III CF?

Answer 41

Defective regulation

Question 42

What's class IV CF?

Answer 42

Decreased conductance

Question 43

Describe very briefly the CF class I situation

Answer 43

Stop codon somewhere, major truncation.

Question 44

Describe very briefly the CF Class II situation

Answer 44

Failure to mature, degradation by proteases.

Question 45

What's the name of the goo the airway cilia flap around in called?

Answer 45

Airway surface liquid (ASL)

Question 46

In CF, what channel is also fucked either directly/indirectly because of screwed CFTR? (No one's sure yet)

Answer 46

ENaC | Hyperabsorption of Na+ seen in CF. Worsens the lack of osmotic pressure into the airway surface liquid.

Question 47

In two terms, list the pathophysiological consequences of CFTR mutation?

Answer 47

Decreased mucociliary clearance | Increase bacterial colonisation

Question 48

Why does the mucal viscosity increase in CF?

Answer 48

Less Cl- export (plus high Na+ influx) removes the osmotic gradient.

Question 49

Why can't we study CFTR in mice?

Answer 49

Because they have way more non-CFTR (i.e. Ca/Cl) transporters than us - not in the intestines though. Them mice were constipated.

Question 50

List four diagnostic tools for CF

Answer 50

Nasal potential difference test DNA test Immunoreactive trypsinogen test Sweat test

Question 51

Why do CF newborns have more immunoreactive trypsinogen?

Answer 51

Mucus plugs form in the pancreas, causing a build up and release of trypsinogen into the blood stream.

Question 52

Where is trypsinogen made?

Answer 52

PANCREAS

Question 53

Why do CF patients have saltier sweat?

Answer 53

The CFTR channels on the sweat glands are inward-facing. They remove Cl- from the sweat to make the sweat hypotonic, so we don't sweat out litres at a time. In CF it's broken - sweat/skin stays salty.

Question 54

What's a positive screen for a CF patient in a sweat test?

Answer 54

>60mM

Question 55

Your sweat test cam back at 30mM. So..

Answer 55

Ooooh lucky.

Question 56

Why the electricity for the sweat test? Just for fun?

Answer 56

It's called iontophoresis - it draws pilocarpine into the skin with the solution under the influence of the current. Best way to deliver the drug. Before that they had to do the whole test in a hemispheric chamber.

Question 57

What do we do after the pilocarpine?

Answer 57

Rinse, absorb sweat into a pad for 30 mins, measure the sweaty pad with chloridometer.

Question 58

In the nasal potential difference test, what does the needle electrode in the arm represent? What does the nasal epithelium represent?

Answer 58

The interstitial fluid. | The airway epithelium.

Question 59

6 CF symptoms you can't forget

Answer 59

respiratory difficulty (wheezing, coughing) viscous mucus secretion in the lungs salty skin clubbing of the fingers bronchitis and frequent penumonia. good appetite - poor growth

Question 60

What do we express only in the packaging cell?

Answer 60

env, pol, gag (rpol will be packaged)

Question 61

What do the crop of viruses from the packaging cells contain?

Answer 61

ITRs, transgene and packaging sequence (psy)

Question 62

Why did gene therapy fail for CF?

Answer 62

Delivery to airway epithelial cells was insufficient at doses that didn't elicit immune responses.

Question 63

7 normal treatments for CF you cant forget

Answer 63

1. antibiotics 2. bronchodilators (e.g. ventolin) 3. physiotherapy (bronchial/postural drainage) 4. mechanical percussion 5. mucolytics 6. high calorie diet 7. exercise

Question 64

4 new treatments for CF 2 agonists, elastic dynamite

Answer 64

1. ClC-2 agonists 2. (alternative Cl channels) 2. S-nitroglutathione (aerosolised - shown to increase CFTR maturation) 3. targeting other ion transport to improve the elastic properties of the mucus 4. Genistein - a CFTR agonist

Question 65

How big is the CF gene? Big enough to fit in an adenovector (for example?)

Answer 65

1.48kDa - yep.

Question 66

What lipid metabolism genetic disorder is low HDL?

Answer 66

TANGIER's. | Foam cells in the tonsils, foam cells all over the place.

Question 67

What's the molecular basis for Tangier's disease?

Answer 67

Defective ABCA1 transporter. | Severely reduced reverse cholesterol transport.

Question 68

What are the two long names for Tangier's disease?

Answer 68

Familial alpha-lipoprotein deficiency. | Hypoalphalipoproteinaemia.

Question 69

What's the ACBA1 transporter do again?

Answer 69

It exports cholesterol from foam cells to HDL.

Question 70

What's a preloaded HDL called again?

Answer 70

Apo-A1 protein

Question 71

What are symptoms of Tangier's disease? (Apart from low HDL)

Answer 71

``` Huge, orangy-yellow tonsils Splenomegaly Hepatomegaly Corneal clouding Slight triglyceridaemia Premature atherosclerosis NEUROPATHY ```

Question 72

The three arms of Pendred Syndrome

Answer 72

Goiter Partial organification problems Sensorineural hearing loss

Question 73

Pendred caused by a mutation in ....

Answer 73

PENDRIN

Question 74

Pendrin is a member of the ________ family of anion transporters.

Answer 74

SLC26A

Question 75

The only disorder in this whole lecture not to be autosomal recessive is...

Answer 75

Romano-Ward LQTS.

Question 76

DO PENDRED.

Answer 76

A