NOTE: There are a few slides from last week we will discuss before these.

1. NOTE: There are a few slides from last week we will discuss before these.

2. Factors Affecting Nerve Transmission • Myelination: • Axon Diameter:

3. Propagation of the AP • Most motor neurons are myelinated by a fatty substance which insulates the membrane • The myelin sheath is made by Schwann cells and is not continuous • The gaps in the sheath are called nodes of Ranvier • AP’s “jump” from one node to the next – this is called saltatory conduction

4. Unmyelinated Neuron +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- Myelinated Neuron +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- +- Direction of AP propagation 

5. Fig 3.3

6. Synapse • In order for neural impulses to be passed from one neuron to the next, they must “communicate” across a synapse • A synapse includes: • The axon terminals of the neuron carrying the impulse • Some transmitting agent (neurotransmitter) • Receptors on the second neuron • The space between these two (synaptic cleft)

7. Synapse

8. Synapse • Most common type is a chemical synapse • Involves release of a neurotransmitter from the axon terminals – many identified  e.g. acetylcholine (Ach) • Following transmission of the impulse, the neurotransmitter is either degraded or actively transported back to the presynaptic terminals

9. Neuromuscular Junction (NMJ) • The NMJ functions in the same manner as a synapse, but is between a nerve and a muscle fibre • The a-motor neuron axon terminals extend into trough-like segments in the sarcolemma called motor endplates • Receptors for neurotransmitters, Ach in particular are found at the motor endplate

10. Neuromuscular Junction (NMJ) Fig 3.5

11. Initiating Contraction • When Ach binds to its receptors (ligand sensing channels) on the sarcolemma, a change in receptor shape occurs which allows Na+ to move across the membrane • As Na+ moves in, the membrane becomes depolarized – this is called the end plate potential (EPP) • If a sufficient EPP occurs, sarcolemma “voltage gated” Na+ channels nearby will open leading to an AP

12. Initiating Contraction • AP spreads across the sarcolemma and into the Tranverse (T)-tubules. • T-tubules carry the impulse deeper into the muscle fibre and initiates the events causing contraction • During repolarization, the muscle fibre is unable to fire again just as in the neuron – this is the refractory period and this limits a motor unit’s firing frequency

13. Excitation-Contraction Coupling • To initiate contraction, Ca2+ must be released into the sarcoplasm by the sarcoplasmic reticulum (SR) • This process is called Excitation-Contraction Coupling (ECC) and it involves: • Depolarization of the T-Tubules • Diffusion of Ca2+ from the SR to the myofilaments Inside the muscle cell (myocyte) Inside the SR Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca

14. Initiating Contraction Fig. 1.7

15. What triggers Ca2+ release? • Somehow, the neural impulse traveling down the T-tubule needs to be communicated to the SR • This occurs at the triad

16. ECC – The Triad

17. T-tubule Feet ECC – The Triad SR

18. ECC – The Triad The ‘Feet’ are composed of 2 types of Ca2+ channels: • The Dihydropyridine Receptor (DHPR) • L-type channel • Located on the t-tubule, voltage sensitive 2. The Ryanodine Receptor (RYR) • located on the terminal cisternaeof the SR

19. Muscle Fibre

21. extracellular ECC – The Triad + - + - + - + - + - DHPR (Voltage Sensor) + - + - + - + - + - RyR Contraction Intracellular (sarcoplasm) Ca Ca Ca Ca Ca Inside SR Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca Ca

22. Muscle Fibre Action • Contraction is initiated by a nerve impulse! • Nerves that cause movement (i.e. an a-motor neuron) may connect with a number of muscle fibres • Collectively, a motor nerve and all the fibres it supplies is called a motor unit

23. Motor Units

24. Motor Units

25. Muscle Fibre Action Basic sequence of events leading to contraction:

26. What happens when calcium is released from the sarcoplasmic reticulum?

27. Role of Ca2+ • To initiate contraction, 4 Ca2+ ions bind to Troponin C • This initiates a conformational change that lifts tropomyosin away from actin, thus exposing the myosin binding sites • The myosin heads, also called the cross-bridges, can now bind to actin

28. Role of Ca2+

29. Mechanism of Muscular ContractionThe Sliding Filament Theory

30. Mechanism of Muscular Contraction Sliding filament theory sarcomere sarcomere I-band A-band A-band Z-disk Z-disk Z-disk Rest Thin filament (actin, troponin, tropomyosin) Thick filament (myosin)

31. The Sliding Filament Theory • When the cross-bridges are bound strongly with actin, they undergo a conformational change • The myosin head tilts toward the arm of the cross-bridge and “drags” the actin • The tilt of the myosin head is known as a power stroke – this causes the sarcomere shortening associated with contraction

32. The Power Stroke • The myosin head is responsible for the actual movement of contraction • The myosin head functions as an ATPase enzyme – the hydrolysis (breaking) of ATP provides the energy needed for the power stroke

33. The Power Stroke ATP ADP Pi Ca

34. The Power Stroke 1. “Attached” • without any energy, the myosin remains attached very tightly to actin • this is the rigor complex and is short lived

35. The Power Stroke 2. “Released” • ATP enters the pocket on the back of the myosin head • This leads to a decrease in the binding affinity for actin, and the myosin head detaches

36. The Power Stroke 3. “Cocked” • The ATP pocket closes and the myosin head again changes shape which causes it to move 5nm further down the actin filament • ATP hydrolysis occurs, but the products – ADP and Pi – remain tightly bound in the pocket

37. The Power Stroke 4. “Force-Generating” • Myosin reattaches to actin (5nm further down the filament than the original site) • Initially, this binding is weak, but the release of Pi causes a conformational change in the head which: • Strengthens the attachment of myosin • Initiates the power stroke

38. The Power Stroke 5. “Attached” • ADP is released during the power stroke • Myosin is attached in the rigor complex, the ATP pocket is open and waiting for a new cycle to begin

39. The Power Stoke ATP ADP

40. Active State • When myosin cross-bridges are attaching to actin, the muscle is in its active state • When myosin is bound to actin, it is sometimes referred to as actomyosin • Duration (speed) and intensity (how many attachments) of the active state depends on the concentration of Ca2+ around the filaments.

41. End of Muscle Action • Contraction stops when nerve impulses to the fibre cease • Ca2+ is removed from the cytoplasm, allowing troponin and tropomyosin to return to their resting state • Myosin binding site is again blocked

42. SR Ca2+-ATPase • aka SERCA or SR Ca2+-pump SR Ca DHPR Ca Ca RyR Ca Ca Ca Ca Ca Ca Ca SERCA SERCA SERCA SERCA ATP ATP ATP ATP CONTRACTION sarcoplasm

43. SR Ca2+-ATPase • Occupies ~ 90% of the SR membrane (few, if any on terminal cisternae) • In resting muscle, ~ 70% of Ca2+ in the cytosol is removed by the SR Ca2+-ATPase

44. Muscle Fibre Action Basic sequence of events leading to contraction:

45. Important Contractile Properties There are 2 major relationships that affect the outcome of muscle contractions: • The length-tension relationship • The force-velocity relationship

46. The Length-Tension Relationship • In the sliding filament hypothesis, each cross-bridge is an independent force generator • Therefore, the force of contraction depends on how many cross-bridges are formed • The degree of actin-myosin overlap in the sarcomere affects the number of cross-bridges • Muscle length affects this relationship

47. The Length-Tension Relationship

48. The Length-Tension Relationship • General model (at the sarcomere or single fibre): Tension (N) Sarcomere Length • there is an optimal length for maximum force production

49. Peak Tension Mechanism of Muscular Contraction Sliding filament theory sarcomere sarcomere I-band A-band A-band Z-disk Z-disk Z-disk Contracted Rest Thin filament (actin, troponin, tropomyosin) Thick filament (myosin)

50. Mechanism of Muscular Contraction Sliding filament theory sarcomere sarcomere I-band A-band A-band Z-disk Z-disk Z-disk Rest Thin filament (actin, troponin, tropomyosin) Thick filament (myosin)