EC Coupling and Calcium II Flashcards Preview

Cardiovascular Unit 1 > EC Coupling and Calcium II > Flashcards

Flashcards in EC Coupling and Calcium II Deck (27):
1

Last phosphorylation one. What happens when troponin is phosphorylated?

It causes calcium to dissociate quicker from thin filaments.

Positive lusitropy.

2

What channel is involved in calcium dependent inactivation (CDI)? What is it that determines the inactivation?

The L-type Ca2+ channel. Its inactivation is dependent on the calcium concentration on the cytoplasmic side of the channel

3

You are given billions of dollars to develop a drug that will treat CPVT. What should your drug do?

A good option would be to design a drug that blocks the RyR2 so that the calcium can't leak. Some drugs have shown some success using sodium channels to block the RyR2.

4

Describe the effect of a phosphorylated DHPR.

There's an increased amplitude of the L-type Ca2+ current. There will also be increased SR storage of Ca2+

The net effect is positive inotropy

5

What does CPVT stand for?

Catecholaminergic polymorphic ventricular tachycardia.

6

What have the TS2 mutations proven to suppress?

They suppress voltage-dependent inactivation, potentially this is what causes the prolonged QT interval and the prolonged ventricular action potential.

*prolonged QT interval is bold in the PDF

They have long QTs because the calcium doesn't turn off

7

What mutation is associated with CPVT?

Causative mutations have been found in the RyR2 which increases "calcium leakiness".

Mutations have also been found in the lumenal calcium buffer calsequestrin which is thought to regulate RyR2 in addition to serving as a buffer.

8

I experience an acute influx of calcium into a myocardial cell that exceeds the efflux of calcium from that same cell. What will happen within the cell? 

The increased calcium within the cell will result in an increased amount of calcium taken up into the SR. Conversely, had the efflux exceeded the influx the amount of calcium in the SR would be decreased.

9

PKA activation is one of the end results of beta adrenergic receptor activation. What are the 4 important targets of PKA in myocardium?

1) The L-type voltage gated Ca2+ channel (DHPR)

2) RyR2

3) Phospholamban (a regulator of the SERCA2 pump)

4) Troponin

10

T or F?

CPVT is only detected on ECGs at rest

False.

It is only detected on ECGs upon exercise of infusion of catecholamines. As you'll see on another card, catecholamines are what contribute to the abnormalities.

11

What's difficult in trying to link phenotypic alterations to genotypic alterations in the heart?

Model systems are required.

Mice aren't the best option to use because mice hearts beat a lot faster than human hearts.

It usually takes a long time for heart problems to express themselves, so other things may have happened in the heart during that lag.

Basically the models aren't perfectly relatable to our hearts.

12

What other non-heart related issues do people with Timothy syndrome typically have?

Intermittent hypoglycemia, immune deficiency, and cognitive abnormalities including autism.

13

A myocardial cell is releasing an increased amount of calcium released via RyR2 (ie more Ca2+ in the SR). How will the CDI process respond?

There will be increased CDI, meaning less calcium will be taken in through the L-type channel (DHPR).

14

T or F?

In CPVT, the problems arise during the "plateau" point at which the maximum amount of calcium is entering through the L-type channel in response to beta adrenergic receptor activation.

False.

Sorry if that was confusing. The problems (calcium release) actually occur shortly or long after repolarization. As a result, calcium is extruded from the cell via the NCX which results in an unintended depolarization that can lead to ectopic action potentials or arrhythmias.

15

What 2 effects will be seen on the heart upon activation of the beta adrenergic receptors?

Increased  contractile force (positive inotropy) and increased rate of relaxation (positive lusitropy) 

16

Ok, so phospholamban (PLB) is now phosphorylated by PKA. What happens?

When PLB gets phosphorylated it stops interacting with SERCA2. So with nothing inhibiting SERCA2, the amount of calcium pumped into the SR increases, and thus SR calcium increases.

Positive inotropy AND positive lusitropy.

17

What are the 2 variants of Timothy Syndrome and what mutations do they arise from?

1) TS. This is a mutation in G406R in exon 8A

2) TS2. a mutation in G402S or G406R in exon 8.

*these seem super specific but I thought I'd include them

18

Which syndrome is associated with a lot of ECG alterations and is also known as Sudden Unexplained Death Syndome?

Brugada syndrome. 

It's brutal that these people die suddenly and unexpectedly.

19

What is the recurrent de novo mutation associated with Timothy syndrome?

Mutations in the Cav 1.2 subunit of the L-type voltage channel (DHPR). That's why there are commonly problems seen throughout the body since Cav 1.2 is in other places besides the heart.

20

On what two calcium concentrations is CDI dependent?

1) The amount of calcium released via the RyR2 receptor

2) The amount of calcium passing through the L-type voltage gated calcium channel

*The RyR2 determined calcium is more important for CDI

21

What mutations can be involved in Brugada syndrome?

Nav 1.5 mutations (phase 0 of cardiac AP), KChip2 (associated with the transient outward current), and ankyrin (which links Nav 1.5 to the cytoskeleton)

*Some have a mutation of Cav 1.2 or the beta subunit of that. Both of these reduce the size of the calcium current. Shorten Q-T.

22

Your RyR2 just got phosphorylated. Now what?

There's an increased sensitivity to activation by calcium.

Positive inotropy.

23

What is the end goal of CDI?

To maintain calcium homeostasis by maintaining a constant SR calcium content.

24

What cardiac problem is associated with syncope, cardiac arrhythmias, and sudden death?

Timothy syndrome

25

What is the hallmark ECG finding in Brugada syndrome?

Shortened Q-T interval

26

In terms of conduction and the ECG, what are common findings in Timothy syndrome?

They tend to have AV block,  prolonged QT intervals (indicative of a prolonged ventricular AP), and episodes of polymorphic ventricular tachycardia.

 

27

Reader's Digest version: What's the problem in CPVT?

The SR is releasing calcium at a pretty random time, not in response to the normal RyR2 activation, and that calcium gets kicked out via the NCX exchanger. As a result, you have depolarization at the wrong time which leads to ectopic APs or arrhythmias.