Cardiac EC coupling and Calcium

Question 1

What are the events that occur during excitation/contraction of cardiac muscle?

Answer 1

action potential spreads into t system• Ca2+ enters via DHPR (“L-type Ca2+ channel”) and activates RyR2 to cause a much larger flux of Ca2+ from SR into myoplasm.• Ca2+ activates contraction by binding to troponin on thin filaments.

Question 2

What are the events that occur during relaxation of cardiac muscle?

Answer 2

• Ca2+ is removed from the myoplasm by:

(i) SERCA2 pump located in longitudinal SR (2 Ca2+ per cycle); Ca2+ diffuses within SR to terminal cisternae, where it binds to calsequestrin (low affinity, high capacity) (MOST IMPORTANT)
(ii) NCX Na+/Ca2+ exchanger in junctional domains of plasma membrane and t-tubules. (iii) PMCA pump in surface membrane (1 Ca2+ per cycle)

Question 3

Compare EC coupling in cardiac vs. skeletal muscle

Answer 3

BOTH: contraction elicited by increase in intracellular Ca, SR is main source of Ca, release of Ca originates at junctional SR or T-tubules. CARDIAC: ECC requires external Ca, Ca released from SR via RyR2, DHPR: CaV1.2. SKELETAL: ECC does NOT require entry of external Ca, Ca released from SR via RyR1, DHPR: CaV1.1

Question 4

Describe the The NCX sodium/calcium exchanger

Answer 4

exchanges 3 Na for 1 Ca and can run either direction depending on membrane potential and Na/Ca gradients.

Question 5

What is the equation that describes the reversal potential for the NCX exchanger?

Answer 5

Vr= 3E(Na)-2E(Ca) where Vr= membrane potential where transport reverses direction

Question 6

Why does extrusion of Ca from cytoplasm via NCX cause membrane depolarization?

Answer 6

If Ca is increased in the cell, the NXC exchanger will extrude Ca, with the consequence of 3 Na being pushed into the cell for ever 1 Ca that is extruded. This creates an overall, inward current and depolarization occurs.

Question 7

NCX driven depolarization secondary to diastolic SR Ca release may play a role in what?

Answer 7

Pacemaking of SA nodal cells and delayed afterdepolarizations that give rise to arrhythmias

Question 8

In short term, what happens when calcium influx exceeds efflux?

Answer 8

Amount of Ca stored in SR increases

Question 9

In short term, what happens when calcium efflux exceeds influx?

Answer 9

SR Ca content decreases

Question 10

Discuss Ca homeostasis

Answer 10

In the long term, calcium entry into myocardial cells from the extracellular space must equal efflux of calcium into the extracellular space. Short term changes in the SR can occur, but over time the SR Ca content must be kept consistent

Question 11

Mechanisms for Ca homeostasis

Answer 11

NCX Ca exchanger, L-type Ca channels

Question 12

How do L-type Ca channels maintain homeostasis?

Answer 12

Calcium-dependent inactivation: this channel undergoes a inactivation that depends on the concentration of Ca2+ near the cytoplasmic side of the channel. If the amount of Ca increases, less Ca is let through the L-type Ca channel

Question 13

What effects do norepinephrine and epinephrine have on the heart

Answer 13

1. Increase Heart Rate (positive chronotropy) by raising the firing rate of pacemaker cells in the SA node 2. Alter propagation through the conduction pathways
2. Increase Contractile Force (positive inotropy)
3. Increase Rate of Relaxation (positive lusitropy)

Question 14

Increased contraction strength and rate of relaxation are caused by stimulation of ___________

Answer 14

Beta adrenergic receptors

Question 15

Which actions of Protein Kinase A contribute to positive inotropy? Positive lusitropy? Both?

Answer 15

inotropy: phosphorylation of L-type Ca channel and RyR2. Lusitropy: phosphorylation of troponin. Both: phosphorylation of Phospholamban

Question 16

Clinical aspects of Timothy syndrome?

Answer 16

Patients have congenital heart disease, intermittent hypoglycemia, immune deficiency and cognitive abnormalities.

Question 17

Genetic defects in Timothy syndrome

Answer 17

recurrent, de novo mutations in CaV1.2 (the principle subunit of the L-type Ca2+ channel), in both the heart as well as other tissues. TS and TS2 mutations display AV block, prolonged QT intervals and ventricular tachycardia. TS2 mutations also suppress voltage dependent inactivation

Question 18

Brugada syndrome

Answer 18

Mutations in cardiac sodium channel, KChip2 (modulatory protein involved in Ikto), etc. Some have mutations in principle subunit CaV2.2 or main accessory subunit beta2b of L-type Ca channel and have a shortened QT interval due to reduction in the magnitude of L-type Ca current

Question 19

ECG abnormalities in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).

Answer 19

Normal ECG at rest, with abnormalities during exercise or infusion of catecholamines

Question 20

Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).

Answer 20

Mutations in RyR2(increases resting leak of Ca from SR or makes RyR2 more sensitive to activation) and calsequestrin2 (reduced buffering of Ca)

Question 21

Mechanism whereby CPVT mutations, in combination with activation of b-adrenergic receptors, causes ectopic depolarizations

Answer 21

Activated B adrenergic receptors results in increased SR Ca. This combined with the CPVT mutations causes extrusion of Ca via NCX and depolarization can trigger ectopic Aps.