Transport Proteins Flashcards
The Na+/K+ pump uses up how much of the cells ATP?
40%.
bonus: there are thousands of them on each cell.
5 drug types that can bring on long QT
Class III antiarrhythmics, antibiotics, tricyclic antidepressants, cholesterol-lowering drugs, cancer meds.
What happen over QRST?
The ventricles depolarise and contract
What does the T-wave represent?
Ventricular repolarisation.
What does a long QT interval indicate?
Some kind of abnormal after-depolarisation or re-entrant depolarisation.
Recall - are myocardial cells Na-dependent or Ca-dependent?
Na-dependent.
Why is tetanisation of skeletal muscle possible but not cardiac muscle?
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.
Which K+ blocker from PCOL2 is known for leading to Torsade-de-pointes?
amiodarone
Which is phase 3 of the cardiac action potential?
The return from plateau to baseline.
At the end of phase ___, Vm has returned to baseline (by definition).
phase 3
EADs occur in __________.
Late phase 2 or phase 3.
DADs occur in __________.
Phase 4 or late phase 3.
Long QT syndrome is caused by a reduced repolarising (K+) current in types…
1,2 and 5,6
LQTS1,2,5 and 6 are all caused by…
mutations in K+ channels, resulting in reductions in polarising current.
LQTS3 is caused by…
mutation in the Na+ channel, causing late inactivation which acts as a source of late depolarising current.
Which LQTS is caused by late the late inactivation depolarising currents?
LQTS3 i.e. the sodium channels close late.
What is the mainstay treatment of congenital LQTS?
Implanted device i.e. pacemaker.
bonus: also a “cardioverter defibrillator”
What symptoms of LQTS would be described as very “well, what was that then?”
Syncope from TdP.
It resolves spontaneously and the patient comes to usually feeling fine.
Syncope can be fine or…
or the TdP escalates into ventricular fibrillation causing sudden death.
nb on terms: TdP is a ventricular arrhythmia that can deteriorate into v-fib.
What is an obvious thing that can precipitate in irregular rhythms?
HR-increasing stuff, e.g. exercise or emotions.
What form of exercise is especially bad in LQTS?
Swimming
Why is sympathetic stimulation (“andrenergic states”) particularly bad in LQTS?
Because sympathetic stimulation works by increasing L-Ca+ channel activity.
Which LQTS affects calcium channels?
LQTS 8
LQTS 8 affects which channels?
calcium
One more time: which drugs in particular set on LQTS?
Class III antiarrhythmics (K+ blockers).
Which is the recessive LQTS?
My only friend at recess and lunch was my imaginary gerbil Lord Nelson.
Jervell, Lange-Nielson
Which is the dominant LQTS?
Everybody Loves Raymond propogated male dominance, not winning any awards from me.
Romano-Ward
Which is the recessive LQTS?
Jervell, Lange-Nielson
Which is the dominant LQTS?
Romano-Ward
How long is a long QT?
≥ 0.47.sec
Is LQT3 due to early opening or late closing?
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.
CFTR is located on chromosome _.
CFRT: chromosome SEVEN. 7
What is the incidence of LQTS?
1/5000
What is the incidence of cystic fibrosis?
1/2500
How many people carry the CF ∆F508 mutation?
1/25
What’s the most common mutation in CF?
Missing phenylalanine residue at position 508 (∆-F508 )
What’s a medal that CF holds?
Most common autosomal recessive disease in Australia.
Name five organs affected by CF
Airways, intestines, pancreas, liver, reproductive tract
Classes range in awfulness from no synthesis to decreased abundance. What are the classes?
I No synthesis II No maturation III Bad regulation IV Decreased conductance V Decreased abundance.
What’s class II CF?
No maturation
What’s Class III CF?
Defective regulation
What’s class IV CF?
Decreased conductance
Describe very briefly the CF class I situation
Stop codon somewhere, major truncation.
Describe very briefly the CF Class II situation
Failure to mature, degradation by proteases.
What’s the name of the goo the airway cilia flap around in called?
Airway surface liquid (ASL)
In CF, what channel is also fucked either directly/indirectly because of screwed CFTR? (No one’s sure yet)
ENaC
Hyperabsorption of Na+ seen in CF. Worsens the lack of osmotic pressure into the airway surface liquid.
In two terms, list the pathophysiological consequences of CFTR mutation?
Decreased mucociliary clearance
Increase bacterial colonisation
Why does the mucal viscosity increase in CF?
Less Cl- export (plus high Na+ influx) removes the osmotic gradient.
Why can’t we study CFTR in mice?
Because they have way more non-CFTR (i.e. Ca/Cl) transporters than us - not in the intestines though. Them mice were constipated.
List four diagnostic tools for CF
Nasal potential difference test
DNA test
Immunoreactive trypsinogen test
Sweat test
Why do CF newborns have more immunoreactive trypsinogen?
Mucus plugs form in the pancreas, causing a build up and release of trypsinogen into the blood stream.
Where is trypsinogen made?
PANCREAS
Why do CF patients have saltier sweat?
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.
What’s a positive screen for a CF patient in a sweat test?
> 60mM
Your sweat test cam back at 30mM. So..
Ooooh lucky.
Why the electricity for the sweat test? Just for fun?
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.
What do we do after the pilocarpine?
Rinse, absorb sweat into a pad for 30 mins, measure the sweaty pad with chloridometer.
In the nasal potential difference test, what does the needle electrode in the arm represent?
What does the nasal epithelium represent?
The interstitial fluid.
The airway epithelium.
6 CF symptoms you can’t forget
respiratory difficulty (wheezing, coughing)
viscous mucus secretion in the lungs
salty skin
clubbing of the fingers
bronchitis and frequent penumonia.
good appetite - poor growth
What do we express only in the packaging cell?
env, pol, gag (rpol will be packaged)
What do the crop of viruses from the packaging cells contain?
ITRs, transgene and packaging sequence (psy)
Why did gene therapy fail for CF?
Delivery to airway epithelial cells was insufficient at doses that didn’t elicit immune responses.
7 normal treatments for CF you cant forget
- antibiotics
- bronchodilators (e.g. ventolin)
- physiotherapy (bronchial/postural drainage)
- mechanical percussion
- mucolytics
- high calorie diet
- exercise
4 new treatments for CF
2 agonists, elastic dynamite
- ClC-2 agonists 2. (alternative Cl channels)
- S-nitroglutathione (aerosolised - shown to increase CFTR maturation)
- targeting other ion transport to improve the elastic properties of the mucus
- Genistein - a CFTR agonist
How big is the CF gene? Big enough to fit in an adenovector (for example?)
1.48kDa - yep.
What lipid metabolism genetic disorder is low HDL?
TANGIER’s.
Foam cells in the tonsils, foam cells all over the place.
What’s the molecular basis for Tangier’s disease?
Defective ABCA1 transporter.
Severely reduced reverse cholesterol transport.
What are the two long names for Tangier’s disease?
Familial alpha-lipoprotein deficiency.
Hypoalphalipoproteinaemia.
What’s the ACBA1 transporter do again?
It exports cholesterol from foam cells to HDL.
What’s a preloaded HDL called again?
Apo-A1 protein
What are symptoms of Tangier’s disease? (Apart from low HDL)
Huge, orangy-yellow tonsils Splenomegaly Hepatomegaly Corneal clouding Slight triglyceridaemia Premature atherosclerosis NEUROPATHY
The three arms of Pendred Syndrome
Goiter
Partial organification problems
Sensorineural hearing loss
Pendred caused by a mutation in ….
PENDRIN
Pendrin is a member of the ________ family of anion transporters.
SLC26A
The only disorder in this whole lecture not to be autosomal recessive is…
Romano-Ward LQTS.
DO PENDRED.
A
