Chapter 7

Question 1

What determines the contractile force of a cardiomyocyte.

Answer 1

The most important factor is the concentration of calcium. Also important are the the magnitude of Ca2+ concentration increase within the cell and the strength with which this binds the calcium receptors. -Ca2+ binds to troponin resulting in the sliding of the actin and myosin filaments over one another resulting in cell shortening - ie contraction

Question 2

Which of the factors that determine the force of contraction is under some degree of genetic regulation?

Answer 2

The strength of calcium binding to the cell.

Question 3

Why is it important that calcium concentrations drop quickly within the cell?

Answer 3

Ca binding to troponin allows actin and myosin to slide over each other and contract during systole. However, diastole depends on the fast detachment and drop in intracellular calcium concentrations allowing the contractile apparatus to relax.

Question 4

How does depolarisation affect calcium concentrations within the cell?

Answer 4

Depolarisation opens L-type Ca channels which are located in the T-tubules.

Question 5

How do L-type calcium channels have such a profound effect on calcium concentration ?

Answer 5

L-type Ca channels are found in the T-tubules, which are invaginations of cell carcolemma adjacent the sarcoplasmic reticulum. L-type only let a small amount of Ca into the cell, however, this pools into the small space between the sarcoplasm and T-tubules, meaning the local [Ca2+] is very high. This large local increase in [Ca] concentration stimulates ryanodine (Ryr) receptors on the sarcoplasm to release a large amount of calcium. The L-type Ca channels and Ryr receptors are only 15um away from one another.

Question 6

In brief, how is the intracellular calcium concentration rapidly reduced?

Answer 6

1) Ryr close
2) SERCA (SR Calcium-ATPase) pumps Ca from the cytoplasm back into the Sarcoplastic reticulum
3) NCX (Na-Ca channel) pumps Ca out of the cell in exchange for Na

Question 7

What is the Dyad?

Answer 7

This is the T-tubule invaginations creating pockets of cell which contain the sarcoplastic reticulum, Z-line of the myofilaments and mitochondria. This condensed area is what allows for small changes in Ca to have profound changes in Ca concentration and fast changes in contraction.

Question 8

what changes do we see with dyads in heart failure?

Answer 8

• reduction in the number of T-tubules results in the loss of the close coupling of L-type Ca channels and the Ryr.

Question 9

What are orphaned Ryr?

Answer 9

These are Ryr receptors in cells which have lost T-tubules (i.e. heart failure). The loss of Dyads results in a reduction of the syncrocinisity and amplitude of the Ca transient.

Question 10

The concentration of Ryr receptors is thought to determine what?

Answer 10

1) if they form Ca2+ sparks
- larger and more uniformly packed zones
2) if they are involved in the Syncrocinicity of systolic calcium
- large and uniformly distributed through the cell

Question 11

What is thought to happen to Ryr receptor density in heart failure?

Answer 11

The density of the Ryr is thought to shift and increase in the zones where T-tubules density has decreased.

Question 12

Why is it beneficial to have to colocalisation of SERCA2, RYR and NCX receptors?

Answer 12

The colocalisation allows Ca entering the cell to be restricted to a specific space (NCX and SERCA2 work as a firebreak) preventing the Ca from diffusing and affecting RYR in other parts of the cell. Additionally, it allows for the fast sequestration of Ca away from the contractile unit during diastole

Question 13

How may a low energy state affect the Ca sequestration within the dyad ?

Answer 13

SERCA2 need to be phosphorylated to function. Hypophosphorylation, allows Ca to diffuse outside of the dyad affecting other Ryr receptors

Question 14

In a steady state, how much calcium must enter the cell?

Answer 14

An equal amount to that pumped out.

Question 15

How does the cell correct a sudden influx of calcium into the cell and return to the steady state?

Answer 15

1) more intracellular calcium results in increased sarcoplasmic calcium content
2)release of calcium from the sarcoplasm will be greater as this organelle releases more if it contains more
3) Increasing the calcium transient’s amplitude decreases calcium entry into the cell because NCX increases Ca eflux (this works on gradients), and increased Ca results in Ca-dependent inactivation of L-type channels.
4) the net loss of calcium from the cell decreases SR Ca
These events continue until the net Ca influx is equal to eflux

Question 16

what are examples of dihidropyridine receptors?

Answer 16

L-type and T-type Ca channels

Question 17

What is myocardial contraction dependent on?

Answer 17

Amplitude and duration of Ca transients and on the sensitivity of the myofilaments to calcium

Question 18

Why and to what degree is calcium buffered?

Answer 18

Calcium has to be buffered to control contractility. If you need to increase contractility rapidly, you can rely on intracellular buffered Ca to allow for a fast increase in concentration available to torponin. Calcium is buffered in a 1:100 (some say 1:200) ratio - ie for every 1 free Ca there is 100-200 Ca which are buffered.
During contraction though, the availability of free Ca immediately increases and this is obtained from buffered sources.

Question 19

How does the sensitivity of the myofilaments to Ca change during the contraction cycle?

Answer 19

When stretched (i.e. blood filling), the myofilaments become more sensitised to Ca. This allows for increased force of contraction to expel blood. Additionally, there is synchronized Ca release during contraction, and there is a robust re-uptake of the calcium to ensure that contraction is abruptly terminated.

Question 20

What is a Ca spark?

Answer 20

There are small influxes of calcium through L-type/T-type Ca channels during depolarisation. This small calcium influx triggers Ryanodine receptors to release large volumes of Ca - ie they are are like small sparks

Question 21

What role do T-type voltage-gated calcium channels play in excitation-contraction coupling?

Answer 21

They play a negligible role. They are not preferentially located in the Dyads unlike L-type and therefore, do not allow any significant amount of calcium into the cell .