EC Coupling and Calcium II

Question 1

Last phosphorylation one. What happens when troponin is phosphorylated?

Answer 1

It causes calcium to dissociate quicker from thin filaments.

Positive lusitropy.

Question 2

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

Answer 2

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

Question 3

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

Answer 3

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.

Question 4

Describe the effect of a phosphorylated DHPR.

Answer 4

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

Question 5

What does CPVT stand for?

Answer 5

Catecholaminergic polymorphic ventricular tachycardia.

Question 6

What have the TS2 mutations proven to suppress?

Answer 6

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

Question 7

What mutation is associated with CPVT?

Answer 7

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.

Question 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?

Answer 8

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.

Question 9

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

Answer 9

1) The L-type voltage gated Ca²⁺ channel (DHPR)
2) RyR2
3) Phospholamban (a regulator of the SERCA2 pump)
4) Troponin

Question 10

T or F?

CPVT is only detected on ECGs at rest

Answer 10

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.

Question 11

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

Answer 11

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.

Question 12

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

Answer 12

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

Question 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?

Answer 13

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

Question 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.

Answer 14

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.

Question 15

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

Answer 15

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

Question 16

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

Answer 16

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.

Question 17

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

Answer 17

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

Question 18

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

Answer 18

Brugada syndrome.

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

Question 19

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

Answer 19

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.

Question 20

On what two calcium concentrations is CDI dependent?

Answer 20

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

Question 21

What mutations can be involved in Brugada syndrome?

Answer 21

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.

Question 22

Your RyR2 just got phosphorylated. Now what?

Answer 22

There’s an increased sensitivity to activation by calcium.

Positive inotropy.

Question 23

What is the end goal of CDI?

Answer 23

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

Question 24

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

Answer 24

Timothy syndrome

Question 25

What is the hallmark ECG finding in Brugada syndrome?

Answer 25

Shortened Q-T interval

Question 26

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

Answer 26

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

Question 27

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

Answer 27

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.