Lecture 15 – Motor Pathways I: Muscles (the other excitable cells) Flashcards
1
Q
Classification of muscle:
A
- Many, but not all skeletal muscle is attached to bone via tendons
- Skeletal muscle has two main functions: movement and the generation of heat
- You may not have thought about this, but shivering actually does warm you up – it is simply a series of muscle contractions and relaxations and muscle contraction is an exothermic (heat generating) process
2
Q
Skeletal Muscle Structure:
A
Skeletal muscle has a distinct structural organisation. Individual muscle cells are termed myocytes (also known as muscle fibres)
- These are covered with a layer of connective tissue called the endomysium
- Note that it is distinct from the muscle cell membrane, the sarcolemma
- Each muscle fibre is multinucleate and is formed by the fusion of cells during development
- Muscle fibres are grouped into bundles termed fascicles (related to the word fascist – it means bundle of sticks) which in turn are covered with another layer of connective tissue called the perimysium
- The fascicles are then grouped together by a sheath called the epimysium to form the muscle
3
Q
skeletal muscle fibre
A
- The muscle fibre contains bundles of protein filaments known as myofibrils
- Myofibrils are in turn composed of bundles of protein filaments called myofilaments
- There are “tunnels” called T tubules leading off from the sarcolemma (cell membrane)
- These tunnels lead into the interior of the muscle fibre and mean that the membrane has a very high surface area
- The second thing to notice is that the endoplasmic reticulum (called the sarcoplasmic reticulum in muscle cells) wraps around the myofibrils
- Specialised parts of the sarcoplasmic reticulum, called the terminal cisternae, interact with the t tubules to form a structure called a triad
4
Q
The Sacromere:
A
H zone: thick filaments not overlapping thin
A band: length of an entire thick filament
I band: where the thin filaments do not overlap thick
5
Q
The Sarcomere: origins of the striations:
A
- There are two major structural features: thick filaments (composed of myosin and titin) and thin filaments composed of actin and nebulin
- Both filaments proteins are connected to the Z disk (alpha actinin) and the thick filaments are also connected to the proteins of the M line in the centre of the sarcomere
- Titin and nebulin have important structural roles in the sarcomere
- Pattern of stripes seen in skeletal muscle depends on how much the muscle is contracted
- This is because the mechanism of contraction involves the filaments sliding over one-another and thus the degree of overlap changes
6
Q
Myosin:
A
¥ Highly diverse family of MOTOR proteins
¥ Skeletal muscle myosin is myosin type II
(different kinds of myosin II in cardiac/smooth)
¥ Myosin head has ATPase activity
¥ Motor powered by hydrolysis of ATP
7
Q
Actin:
A
It exists in two forms: a globular form: G actin and a filamentous form: F actin. F actin is a helical protein (single stranded) and is the form of actin found in muscle.
8
Q
Troponin and Tropomyosin:
A
- In skeletal muscle actin is associated with several other proteins that play key roles in the regulation of muscle contraction.
- Tropomyosin runs along the actin chain. It consists of two alpha helical chains that coil around each other. 1 tropomyosin interacts with 7 actin monomers.
- Troponin is a complex of three proteins Troponin T, I and C. Each is named for its function. There is one troponin trimer per tropomyosin molecule.
- Troponin T binds to tropomyosin. Troponin I binds to actin and inhibits contraction. Troponin C binds calcium. Together, the complex allows the contraction of muscle to be regulated by calcium. We’ll see how this happens in a few slides time, but first, we are going to look at how contraction actually occurs.
9
Q
Troponin and Tropomyosin 2:
A
- In stage 1, myosin is bound to actin (attached state)
- Stage 2 occurs when the myosin head binds ATP
- This causes the dissociation of the myosin-actin bond
- Stage 3: the myosin head has a built in ATPase activity. When it breaks down ATP to ADP and Pi, the conformation of the myosin changes and it enters the “cocked state”
- Stage 4 involves the formation of a new cross bridge between actin and myosin two actin monomers further down the chain N.B. no movement of the muscle has occurred yet
- Next (Stage 5), the phosphate is released and the POWER STROKE occurs. This is caused by a conformational change of the myosin back to the uncocked state. Finally, the ADP is released and the system is back to the starting state. However, the actin and myosin have moved relative to one another – the muscle has contracted.
10
Q
Regulation of Contraction:
REST
A
- At rest, the tropononin trimer sits so that TnI inhibits the formation of actin-myosin cross bridges – it blocks the interaction by covering up the myosin binding site.
11
Q
Regulation of Contraction:
CONTRACTION
A
- However, when muscle contraction is signaled (more on that in a moment!), Ca2+ concentrations increase
- Ca2+ can now bind to troponin C
- This triggers a change in conformation of troponin and tropomyosin
- Tropomyosin moves deeper into the actin groove whilst the troponin complex shifts up, revealing the myosin binding sites on the actin
Cross bridges can now form
12
Q
Excitation Contraction Coupling (NMJ revisited):
A
Motor neurones synapse with muscle in specialised structures known as neuromuscular junctions, or end plates
- Motor neurones release ACh into the synapse, this binds to nicotinic acetylcholine receptors on the muscle membrane, which open, allowing sodium ions to flood into the muscle and depolarise the membrane
- Somehow this depolarisation is then translated into a calcium signal that can start the actin-myosin cross bridge formation that we looked at over the previous slides
13
Q
NMJ 2:
A
The t tubules are tightly apposed to the sarcoplasmic reticulum(SR) of the muscle fibre
- Where it makes contact with the t tubule, the SR is bulbous, forming a structures termed terminal cisternae
- Two terminal cisternae are associated with each t tubule – together this structure is known as a triad
- The SR is not continuous with the t tubule: the SR is an intracellular organelle and the t tubule is part of the cell membrane
14
Q
Calcium in Muscle Cells:
A
If one measures the concentration of calcium in the extracellular fluid, it is a few mM
- In the cytoplasm though, it is around 10000-fold lower. However, if we look inside the sarcoplasmic reticulum, we find similar concentrations to the extracellular fluid
- It turns out that the asymmetric distribution of ions inside the muscle is because the there are calcium ATPase pumps (like the sodium pump) in the membrane of the sarcoplasmic reticulum that actively pumps calcium ions into the SR. This pump is known as SERCA (Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase)
- When you think about it, it is sensible that the cytoplasmic concentration of calcium is low: if it were not, then the muscle would be permanently contracted.
- However, to get the muscle to contract at all, we need to be able to increase calcium concentrations to a level sufficient to activate troponin
- One possibility is that the calcium enters via voltage sensitive calcium channels in the muscle membrane that open in response to an action potential
- In skeletal muscle, calcium can certainly enter the cytoplasm via this route
- However, experiments have shown that this type of entry is of secondary importance and is not necessary to trigger contraction
15
Q
Where does the calcium come from to trigger contractions?
A
- The other big pool of calcium of course is in the SR
- It turns out that the SR also has calcium channels
- These are of a different type to those found in the membrane and are linked to the VSCC found in the T tubules via a physical connection
Note that the VSCC here has a couple of different names – it is known as an L-type VSCC but also as the dihydropyridine receptor
