Lecture 5/6 - Cardiac Muscle function

Question 1

Describe how Ca2+ allows for muscle contraction?

Answer 1

Ca2+ binds to and changes the conformation of tropomyosin, this exposes the binding site for the myosin head. This allows for actin-myosin interaction, and then the powerstroke of the myosin head occurs then tension is developed.

Question 2

Describe the sequence of events of when the cell is depolarised until Ca2+ enter the cell.

Answer 2

The cardiomyocyte is depolarised via a gap junction from an adjacent cell.

The membrane potential rises, and once threshold has been reached the L-type Ca channels open - and then Ca2+ enter the cell.

However this movement of Ca2+ is not enough alone to cause contraction, we need to also get Ca2+ from the sarcoplasmic reticulum sotres.

Question 3

Once Ca2+ has entered the cell through L-type Ca chanels, what happens?

Answer 3

Ca2+ ions that enter the cell trigger the release of Ca2+ ions from the intracellular Ca2+ store in the sarcoplasmic reticulum.

Ca2+ does this by binding to Ca2+ release channels called a ryanadine receptor, this causes calcium induced calcium release (CICR) as a result.

Ca2+ are released from the SR, increasing the intracellular conc. 10-100 fold.

Question 4

Once Ca2+ is released from SR Ca2+ stores, what happens next?

Answer 4

Ca2+ ions bind to troponin C in the troponin complex.

This changes the shape of tropomyosin, which exposes the binding site for the myosin head. This then binds, allowing for actin-myosin interaction to occur -> leading to muscle contraction.

Question 5

How does cardiac muscle relax?

Answer 5

At the end of contraction the Ca2+ influx stops and the SR is no longer stimulated to release Ca2+.

The intracellular concentration needs to be reduced rapidly to relax the muscle.

Question 6

Out of the 3 different mechanisms to reduce intracellular Ca2+,

how does SERCA work?

Answer 6

1. SR ATP-dependent Calicum pump (SERCA)

• SERCA is an ATP dependant pump which pumps Ca2+ from the cytoplasmic back into SR stores.
  
  • SERCA activity is regulated by the regulatory protein phospholamban (PLN) which inhibits Ca2+ re-uptake into the SR store (in unphosphorylated state)

Question 7

For the second mechanism for reducing intracellular Ca2+ concentration, how does the sodium-calcium (Na+-Ca2+) exchange pump work?

Answer 7

Pumps 3 Na+ into the cytoplasm, whilst pumping 1 Ca2+ back into the SR

This is powered by the Na+ gradient

Question 8

For the third mechanism for decreasing intracellular Ca2+ in cardiac muscle, how does the cell membrane ATP-dependent Ca pump work?

Answer 8

Uses ATP to pump out Ca2+ outside of the cell

Question 9

So, what are the three mechanisms for reducing intracellular Ca2+ following cardiomyocyte contraction?

Answer 9

1. SERCA pump
2. Na+-Ca2+ exchanger (also on cell membrane)
3. Cell membrane ATP dependant Ca2+ pump

Question 10

Which of the three mechanisms does most of the work?

Answer 10

SERCA pumps most of the Ca2+ back into the SR by SERCA.

Most of the remaining Ca2+ is extruded through the cell membrane by the Na-Ca exchanger.

Only a smaller amount is pumped out of the cell by ATP dependant Ca2+ pump (Ca-ATPase)

Question 11

What affect does sympathetic stimulation have on muscle contraction and relaxation?

Answer 11

Causes an increase in active tension.

And it increases the rate of tension developent, as well as increasing the rate of relaxation (allow for a shorter contraction).

Question 12

How does beta1 adrenergic receptor stimulation via sympathetic activity have a positive inotropic effect?

Answer 12

NA binds to beta1 adrenergic receptor.

This increaes cAMP, which activates protein kinase A. This phosphorylates L-type Ca channels, causing there to be an increase in inwards Ca2+ current, and also phosphorylates the RyR channel.

This means that more ions enter the cell during depolarisation, and this increased Ca2+ conc. increases the force of contraction.

Sympathetic stimulation has a postive inotropic effect on the heart.

Question 13

How does B-adrenergic stimulation by sympathetic activity have a lusitropic effect on the heart?

Answer 13

NA binds to Beta1-adrenoreceptors on the cardiac muscle well.

This increases intracellular cAMP concentrations, which activates protein kinase A (PKA).

PKA then phosphorylates phospholamban (PLN), which reduces inhibiton of SERCA2. Therefore phosphorylation of PLN increases the rate of relaxation (lusitropic effect).

PKA also phosphorylates troponin-I, this limits the interaction between troponin-C and Ca, causing relaxation.

Question 14

What does total tension of the heart consist of?

Answer 14

Both passive and active tension together.

Passive tension is the tension we get when we just pull on it, it’s the recoil if we try pull the tissue itself.

Active tension is when the fibres are working, active tension varies with length

Question 15

What happens if the muscle is overstretched?

Answer 15

It’s ability to produce active tesnion is reduced

Question 16

What is Starling’s Law?

Answer 16

If LVEDV increases, the left ventricle responds increasing its stroke volume.

Question 17

What is contractility?

Answer 17

It describes cardiadc performace at a given preload and afterload.

Every point on the starling curve has the same contractility

Question 18

What happens to the starling curve if there is an increase in contractility?

Answer 18

We shift to a high starling curve

This means we have a higher SV for a given EDV.

Question 19

What are inotropic agents?

Answer 19

Agents that cause in increase in contractility have a positive inotropic effect.

e.g. NA, adrenaline: increase Ca2+ influx and uptake by SR -> increased intracellular Ca2+

Digoxin: increases intracellular Ca2+ (blocks Na/K pump which slows Na-Ca exchanger)

Agents that cause a decrease in contractility have a negative inotropic effect.