Lecture 4 Flashcards
What are the three stages of excitation contraction coupling in regards to Ca2+?
- Ca2+ entry
- contraction
- relaxation/ Ca2+ uptake
How does Ca2+ enter the cell?
There is an action potential and the cell membrane depolarises. The membrane potential rises. The threshold of L-type Ca2+ channels is reached and these open. Ca2+ enters. This binds to the ryanodine receptor on the sarcoplasmic reticulum. This promotes further release of Ca2+ from the SR stores. The [Ca2+] in the cell increases hugely
Why is the calcium induced calcium release really efficient?
because the ryanodine receptor and L-type Ca2+ channel are really close in space so the diffusion distance is really small
What percentage of the calcium comes in via the L-type receptor and what percentage comes in via the ryanodine receptor from the SR?
25% from the L-type calcium receptor and 75% from the SR
In cardiac muscle, depolarisation causes what to happen?
Ca2+ induced Ca2+ release
How does Ca2+ drive contraction?
Ca2+ binds to troponin C in the troponin complex. Tropomyosin moves to allow an actin/myosin interaction and there is muscle contraction
What are the three troponin compounds that make up a troponin complex?
Troponin C
Troponin I
Troponin T
What is Troponin C?
This is the Ca2+ binding domain
What is Troponin I?
the inhibitory domain
What is Troponin T?
the tropomyosin binding domain
Briefly describe sarcomere shortening
Initially, the actin binding sites are blocked.
Ca2+ binds to the Troponin C. There is movement of the troponin/tropomyosin complex exposing the myosin binding site on actin. There is interaction between actin and myosin (cross-bridge).
The myosin head flips. The actin moves towards the centre of the sarcomere. The sarcomere shortens
When the sarcomere shortens, do actin and myosin also shorten?
no
Describe the cross-bridge cycle with relation to the ATP
- ADP + Pi is bound to the myosin head so myosin has a high actin affinity (but the troponin/tropomyosin complex is still blocking the site so they can’t bind)
- Ca2+ binds to TnC, there is movement of the troponin/tropomyosin complex exposing the myosin binding site on actin and now myosin can bind to the actin
- ADP + Pi is released which causes the myosin head to shift (90° to 45°) and the filaments slide over each other
- [Ca2+] decreases so it dissociates from TnC and so the troponin/tropomyosin complex rotates back to block the myosin binding site
- at the same time, ATP binds to myosin so myosin has a low actin affinity so the cross-bridge detaches
- myosin cleaves ATP to ADP + Pi and the process starts again
Describe the sliding filament theory
Myosin is pulling actin towards the centre of the sarcomere. Actin filaments slide along adjacent myosin filaments by cycling of cross-bridges with myosin. The Z line comes closer together and the cell shortens thus producing force or tension.
What percentage of myosin heads are needed to contract?
20%-40%
How can we produce a more forceful contraction?
You can increase the number of cross-bridges (not increasing the number of cardiomyocytes because all of them are contracting at once)
During contraction of the sarcomere,
A. myosin is pulling actin towards the centre of the sarcomere
B. myosin shortens moving actin towards the centre of the sarcomere
C. Actin shortens causing the z-line to move towards the centre of the sarcomere
D. both actin and myosin shorten
A. myosin is pulling actin towards the centre of the sarcomere (actin and myosin DO NOT shorten)
What are the three different mechanisms to reduce intracellular Ca2+?
- SR Ca2+ pump (SERCA)
- Na+/Ca2+ exchanger (NCX)
- Ca2+ ATPase
Explain how intracellular Ca2+ reduced by the SR CA2+ pump (SERCA)?
This pump uses ATP to pump cystoplasmic Ca2+ back into the SR
What percentage of intracellular Ca2+ is removed by the SR Ca2+ pump?
75%
How is SERCA activity regulated? Explain this
by Phospholamban.
When PLB is bound to SERCA, SERCA is partially inhibited so it takes up Ca2+ more slowly. When PLB is phosphorylated, it can dissociate from SERCA and Ca2+ uptake happens quicker
Explain how the Na+/Ca2+ exchanger (NCX) reduces the intracellular Ca2+ concentration
This is a secondary active transporter which wants to move Ca2+ against its gradient (to the outside of the cell). It uses the Na+ gradient to provide the energy to do this
What percentage of intracellular Ca2+ is removed by the Na+/Ca2+ exchanger (NCX)?
24%
Explain how Ca2+ ATPase reduces the intracellular Ca2+ concentration
This uses ATP to pump Ca2+ out of the cell
What percentage of intracellular Ca2+ is removed by the Na+/Ca2+ exchanger (NCX)?
1%
Why do we need such a long refractory phase in a cardiomyocyte?
We need to ensure that the myocyte has relaxed before it can be excited again. This is important in the heart so that the cells can fully relax and the heart can fill with blood again
What is the refractory phase?
The cell during the plateau phase is still depolarised so the cell is in-excitable. The cell is already depolarised so if another action potential comes along, it can’t be triggered to depolarise again. Cardiomyocytes have to wait a long time before they can activate again
Why is summation of contractions not possible in the heart?
because each contraction has to partially relax before we move out of the refractory period
We need lots of energy (ATP) for the heart to contract. Where does this come from?
mitochondria
During cardiac metabolism, chemical energy is converted into what?
mechanical energy
Heart needs lots of energy through ATP. How does this happen?
What else is required?
This happens though oxidative (aerobic) metabolism.
This uses fatty acids and glucose as the energy substrates
How does the heart get oxygen for oxidative metabolism?
Through blood supply via the coronary circulation
How is the blood extraction from the coronary supply so high (75%)?
because there is a low partial pressure of O2 in cardiomyocytes which means that O2 diffuses in quickly
What happens if the blood supply to the heart decreases?
it can lead to coronary heart disease
What part needs the ATP?
- SERCA
- deattachement of the actin-myosin cross-bridge
- Ca2+ extrusion by Ca2+ ATPase
- Na+/K+ ATPase
- primary active transport
What happens if you run out of ATP?
You can’t remove all the Ca2+ so it remains high, myosin can’t unbind from actin so there is continued contraction (rigos mortis)
