18-01-22 - Excitation Contraction Coupling in Cardiac and Skeletal Muscle Flashcards
Learning Outcomes
- Explain the role of the transverse tubules, and the terminal cisternae in skeletal muscle contraction
- Explain the role of ‘junctional foot proteins’ and the role of the ryanodine and dihydropyridine receptor binding proteins
- Detail the changes in the cytoplasmic calcium concentration during activation and relaxation
- Explain the importance of Ca-ATPase and calsequestrin
- Detail key differences in excitation contraction coupling between skeletal and cardiac muscle
What is excitation contraction coupling?
How fast is the skeletal muscle action potential?
What is the latent period?
What is the latent period to do with?
What are t-tubules?
What do triads consist of?
How is the action potential brought into the interior of the muscle fibre?
What happens to this change in membrane potential?
- Excitation contraction coupling is the linkage between excitation of the muscle fibre membrane (sarcolemma) and the onset of contraction
- The skeletal muscle action potential is very rapid (around 10ms)
- The latent period is the period from the peak of an action potential to the onset of contraction
- The latent period is to do with the delivery of the depolarisation deep down into the muscle fibres, because the electrical potential occurs in the vicinity of the membrane
- T-tubules (transverse tubules) are invaginations of the cell membrane of muscle cells
- A triad consists of a transverse tubule (t-tubule) sandwiched between 2 terminal cisternae (enlarged areas of sarcoplasmic reticulum)
- Triads are specialised structures that allow the action potential to be delivered deep into the muscle fibre, where the change in membrane potential can be sensed and converted into a mechanical response
Describe the 7 steps in the process in which the action potential is taken deep into the muscle fibre of skeletal muscles and muscle contraction.
What is it that activates this process in skeletal muscles?
What are DHPR and RYR referred to as?
What does the cytoplasmic calcium concentration change to during this process?
What is the key event that ultimately leads to force generation?
1) At the neuromuscular junction, the action potential is propagated from the end plate along the surface of the muscle fibre (sarcolemma)
2) The action potential is propagated into the fibre down the t-tubule membrane
3) Dihydropyridine receptor proteins (DHPR) are L-type voltage-gated calcium channel in the t-tubule membrane. When these DHP receptors sense the change in membrane potential, it causes them to change their conformation, allowing Calcium to move into the cytoplasm of the cell
4) This allows the DHPR to electro-mechanically couple with Type 1 Ryanodine receptor proteins (RYR) on the terminal cisternae of the SR, which activates the ryanodine receptor
5) This leads to the release of calcium from the SR into the cytoplasm of the muscle cell (sarcoplasm) down a steep concentration gradient
6) When the calcium concentration in the cell reaches a certain threshold, Ca2+ binds to TnC (troponin-c), which causes a conformational change in TnI and TnT, resulting in tropomyosin revealing myosin binding sites on actin
7) This allows for strong actin and myosin binding, which leads to muscle contraction
• In skeletal muscles, this process is initiated via the mechanical coupling between DHPR on the t-tubule and the ryanodine receptor (RYR) on the terminal cisternae of the SR
• DHPR and RYR are referred to as junctional foot proteins
• The cytoplasmic calcium concentration changes from <10^-7M to >10^-5M
• The increase in intracellular calcium concentration is the key event which ultimately leads to force generation through the interaction of actin and myosin filaments
What are dihydropyridines?
What is an example?
What 3 things are they used to treat?
What are ryanodines?
What is an example of a ryanodine?
What 2 things are they used to treat?
• Dihydropyridines are voltage-gated Ca2+ channel locking drugs
• Nifedipine is an example of a dihydropyridine
• Dihydropyridines are use to treat smooth muscle:
1) Hypertension
2) Migraine
3) Atherosclerosis
• Ryanodines are spasmolytic drug acting as a skeletal muscle relaxant
• An example of a ryanodine is dantrolene
• Ryanodines are used to treat (SR):
1) Muscle spasm
2) Malignant hyperthermia
What is malignant hypothermia associated with?
What type of disorder is it?
What does it lead to a sever reaction to?
Where does it first manifest?
What is the underlying mechanism of MH?
What are 4 symptoms of MH?
What is administered prior to surgery to treat MH?
- Malignant hyperthermia is associated with Ryanodine receptor type 1 channel mutations
- Malignant hyperthermia is a pharmacogenetic disorder of the skeletal muscle
- MH leads to a severe reaction to commonly used anaesthetics and depolarising muscle relaxants
- MH first manifests in the operating room, and can be fatal if untreated
- Underlying mechanisms of MH are point mutations in the gene coding for RyR1, which causes the receptor to become very active and release sodium into the cell in response to anaesthetic
• Symptoms of MH:
1) Muscle rigidity
2) High fever
3) Increased acid levels in blood and other tissues
4) Rapid heart rate
• A postsynaptic muscle relaxant called dantrolene is administered prior to surgery, which inhibits ryanodine receptors and brings calcium levels back down to normal
What is SERCA?
What activates SERCA?
How does skeletal muscle relaxation occur?
How many molecules of Calcium are transported per molecule of ATP hydrolysed?
What does the cytoplasmic concentration of Calcium drop to?
What is calsequestrin? What is its role?
What is its molecular weight?
How many calcium ions can it bind per molecule?
- SERCA is the Sarcoplasmic Endoplasmic Reticulum Calcium ATPase (Ca2+ ATPase)
- SERCA in the SR membrane is activated by the increase in intracellular calcium concentration during the process of contraction
- Skeletal muscle relaxation occurs when calcium is pulled back into the SR stores via SERCA through active transport, as the calcium goes against its concentration gradient
- 2 calcium ions are actively transported from the cytoplasm to the SR per molecule of ATP hydrolysed
- The cytoplasmic concentration of calcium drops back to
How do skeletal and cardiac muscle cells differ in terms of initiation of contraction?
How is this made possible?
- In skeletal muscle in order to initiate contraction, it needs to be innervated and receive an electrical impulse from the neuromuscular junction
- Cardiac muscles do not need to be innervated to initiate contraction, rather the cardiac muscle is innervated to the control the rate of contraction (autonomic innervation)
- This is made possible by specialised muscle cells located in the SA node called pacemaker cells
What do pacemaker cells undergo?
What does this allow?
What is the resting potential of pacemaker cells like?
What is characteristic of pacemaker potentials?
What is the key event which leads to force generation in the heart muscle?
Describe the 3 steps that cause the contraction of the heart.
Describe the autonomic innervation of the cardiac muscle (parasympathetic and sympathetic), stating the neurotransmitter, action and innervation
- Pacemaker cells undergo automatic rhythmical depolarisation
- This allows pacemaker cells to set the rhythm of the cardiac tissue
- Pacemaker cells have an unstable resting potential
- Pacemaker potentials always depolarise to threshold
- The increase in intracellular calcium concentration from <10^-7M to >10^-5M is the key event which ultimately leads to force generation through interaction of actin and myosin filaments, which causes the contraction of the heart muscle
• 3 steps that cause the contraction of the heart:
1) Pacemaker cells initiate a depolarisation and generate an action potential
2) Electrical signal is propagated down the conduction pathway into the left ventricle
3) The electrical signal is converted into a mechanical response, which causes the contraction of the heart
• Autonomic innervation of the heart:
1) Parasympathetic:
• Neurotransmitter – acetylcholine
• Action – slows rate
• Innervation – localised to pacemakers
2) Sympathetic:
• Neurotransmitter – nor-adrenaline
• Action – increases rate and strength
• Innervation – diffuse
How does the cardiac muscle action potential differ from skeletal muscle action potential?
Describe the cardiac muscle action potential.
What occurs during the plateau?
How does muscle tension during action potential differ between skeletal and cardiac muscle?
• Cardiac muscle action potential (hundreds of ms) is a lot longer than skeletal muscle action potential (about 10ms)
• The cardiac muscle action potential has a rapid depolarisation followd by a plateau period, where we get an extension of the action potential prior to repolarisation
• During this plateau, we get an elevation in the intracellular calcium, which is the key event in force generation
• During skeletal muscle contraction, there is a latent period bewteen the peak of action potential and the onset of muscle tension
• In cardiac muslce, there is onset of muscle tension during the action potential
What is the difference between the interactions between the DHPR and RYR in the skeletal and cardiac muscle?
What are the sources for calcium needed for contraction in cardiac muscle?
What is this process known as?
- The key difference is there is no mechical coupling bewteen the DHPR and the RYR
- In cardiac muscle, 25% of the required Ca2+ enters through the voltage gated L-type Ca2+ channels (DHP receptor protein) in the transverse tubular membrane
- The calcium acts as a ligand for ligand gated RYR channels, resulting in the RYR channels on the SR surface opening, and remaining 75% of calcium required for contraction entering into the cell
- This process is known as Ca2+ induced Ca2+ release (CICR) in cardiac muscle
Describe the 5 steps of the process of excitation contraction process in the cardiac muscle
1) The cardiac action potential is triggered
2) The change in membrane potentials is delivered deep into the muscle fibres by t-tubules, which are iinvaginations of the cardiac muscle cell membrane
3) This change in membrane potential will activate voltage-gated L-type calcium channels (DHP receptor)
4) Calcium will flow into the cell and bind to the type 2 ryanodine receptors on the SR membrane in a process called calcium induced calcium release.
5) Calcium will flow down its concentration gradient from the SR into the cytoplasm, where calcium can bind to the contractile machinery (troponin-c)
Describe the 4 steps of the process of relaxation after contraction in the cardiac muscle
1) After contraction, the calcium is pumped back into the SR stores against its concentration gradient via SERCA pumps
2) Calsequestrin will mop up as much free calcium as it can to try and reduce the concentration gradient of calcium (still an ctive process requiring ATP)
3) Calcium is also extruded from the cell via Ca2+, Na+ exchanger. 3 sodium ions echanged per calcium ion
4) Na+ concentration has to be maintained by the NaK ATPase in order to avoid an unwanted action ptoential from being generated
5) Relaxation occurs when the cytoplasmic calcium concnetration goes from >10^-5M to <10^-7M
