2. RMP, ionic basis, factors affecting RMP AP, ionic basis, characteristics Change in excitability during an action potential Characteristics of local response Functional states of voltage-gated ion channel Summary

3. Chapter 2 Basic Functions of cells 谢俊霞 教授

4. Striated muscle  Skeletal muscle  Cardiac muscle Smooth muscle Striated muscle

5. Anatomy of neuromuscular junction Sequence of events during transmission Characteristics of end-plate potential Factors affecting neuromuscular transmission Neuromuscular transmission

6. Anatomy of neuromuscular junction

7. Prejunctional membrane Synaptic vesicle Active zone Junctional cleft Endplate membrane Junctional fold N 2 -Ach receptor cation channel Acetylcholinesterase Anatomy of neuromuscular junction

8. Sequence of events during transmission

9. Action potential arrives at Prejunctional membrane Action potential causes calcium channels to open (Ca 2+ enters ) Ca 2+ cause synaptic vesicle to move and release Ach Ach diffuses across junctional cleft Ach binds to N2 Ach receptor on endplate membrane Na+, K+ channels open (Na+>K+ ) Causes depolarisation of the endplate membrane (EPP) Action potential is produced in the muscle membrane Sequence of events during transmission

10. End-plate potential (EPP): depolarization of motor end plate of skeletal-muscle fiber in response to acetylcholine; initiates action potential in muscle plasma membrane. Sequence of events during transmission

11. Characteristics of end- plate potential

12. Sequence of events during transmission

13. A1 Transmitter-gated channels Ach binding Channel opening Na+ inflow K+ outflow Depolarization Result: end-plate potential A2 Voltage-gated channels Na+ channel opening Na+ inflow Depolarization Result: action potential Sequence of events during transmission

14. B1 Transmitter-gated and voltage- gated channels are in parallel B2 Effect of transmitter-gated channels on voltage-gated channels

15. Miniature end-plate potential

16. Quantal release

18. Summary - Neurotransmission

19. Nicotinic acetylcholine receptor cation channel

21. Factors affecting neuromuscular transmission Ca 2+ concentration at presynaptic terminal: Ca 2+ chelate Activity of ACh receptor: tubocurarine; α-bungarotoxin Acetylcholinesterase (AChE) inhibitor: pyridostigmine

22. Myasthenia Gravis(MG) Wendy Chu: a 23-yr-old photographer for a local newspaper.Over the last 8 months, she experienced ‘strange’ symptoms: severe eyestrain reading for longer than 15 min, tired when she chewed, brushed, extreme fatigue on the job. Physician initiated a trial of pyridostigmine, an acetylcholinesterase inhibitor, immediately felt better, antibody test was positive,confirming the diagnosis of MG.

23. Myasthenia Gravis(MG) 问题 1. 患者血清中被检查的抗体是什么？ 2. 根据神经肌接头兴奋传递过程，解释为什么重症肌无 力患者有严重的肌肉无力症状。 3. 为什么吡啶斯的明可改善重症肌无力患者肌力 ? 4. 下列药物可作用于神经肌接头传递的各个环节，哪些 药物对重症肌无力是禁忌的？ （ 1 ）肉毒杆菌 （ 2 ）箭毒 （ 3 ）新斯的明 （ 4 ）密胆碱

24. 分析 1. 检测的抗体是抗 N 型乙酰胆碱受体抗体。 2. 重症肌无力患者血液中有异常的抗乙酰胆碱受体抗体，它们会占据骨 骼肌终板膜上的乙酰胆碱受体。此时，生理情况下由运动神经末梢释 放的乙酰胆碱不能和终板膜上受体结合，终板膜不能产生终板电位， 从而影响了骨骼肌细胞膜上动作电位的产生。因而患者有严重的肌无 力症状。 3. 吡啶斯的明通过与胆碱酯酶结合而抑制其活性，减慢了骨骼肌终板膜 上乙酰胆碱的降解，提高了接头间隙乙酰胆碱的浓度，从而延长了其 作用时间。终板膜接触高浓度乙酰胆碱时间越长，骨骼肌动作电位及 收缩能力越强。 4. 总的来说，任何抑制神经肌接头兴奋传递的药物对重症肌无力都是禁 忌的。肉毒杆菌可阻止运动神经末梢释放乙酰胆碱，从而完全阻断神 经肌接头兴奋传递过程，因而是禁忌的；箭毒是骨骼肌终板膜上乙酰 胆碱受体的竞争性抑制剂，可抑制肌纤维去极化，所以也是禁忌的； 新斯的明与吡啶斯的明类似，为胆碱酯酶抑制剂，可通过减少乙酰胆 碱的降解用于重症肌无力的治疗；密胆碱可阻断运动神经末梢重摄取 胆碱，耗竭乙酰胆碱储备，所以对重症肌无力是禁忌的。 Myasthenia Gravis(MG)

25. Myofibril and sarcomere Ultrastructure of striated muscle

26. Sarcotubular system (T tubule) Longitudinal SR, LSR (Terminal cisterna) Triad (T tubule) (Terminal cisterna) (Junctional SR, JSR) (SR) JSR : Ca 2+ release channel (ryanodine receptor,RYR) T tubule : L-type Ca 2+ channel LSR : Ca 2+ pump

27. Myofilament sliding theory: process of muscle contraction in which shortening occurs by thick and thin filaments sliding past each other. Molecular mechanisms of contraction

28. Molecular components of myofilament

29. Process of muscle contraction Cross-bridge cycling

32. The action potential triggers contraction This question has the beginning (AP) and the end (contraction) but it misses lots of things in the middle! We should ask: how does the AP cause release of Ca from the SR, so leading to an increase in [Ca]i? how does an increase in [Ca]i cause contraction? How does the AP trigger contraction?

33. Excitation-contraction coupling: mechanism in muscle fibers linking plasma-membrane depolarization with cross- bridge force generation. Excitation-contraction coupling

34. Intracellular Ca 2+ is the key of excitation-contraction coupling Excitation-contraction coupling

37. Difference of Ca 2+ release between skeletal and cardiac muscle Calcium-induced Ca 2+ release, CICR

38. Time relationships between action potential and the resulting shortening and relaxation of the muscle fiber

39. Time relationships between action potential, intracellular [Ca 2+ ] and twitch tension Calcium transient

40. Calcium transports Na + -Ca 2+ exchanger Cell Endoplasmic reticulum 1 Ca 2+ /ATP 2 Ca 2+ /ATP 3 Na + 1 Ca 2+ Low intracellular Ca 2+ : 0.1~0.2μM Calcium pump Calcium pump

41. Performance of contraction: force; shortening; velocity Isometric contraction: contraction of muscle under conditions in which it develops tension but does not change length. Isotonic contraction: contraction of muscle under conditions in which load on the muscle remains constant but muscle shortens. Factors affecting the performance of contraction

42. Isometric contraction and isotonic contraction Isometric twitch Isotonic twitch Latent period Tension Distance shortened

43. Preload Optimal initial length: the length at which the fiber develops the greatest tension.

44. Afterload

45. Intracellular Ca 2+ level ATPase activity of myosin Contractility

46. Summation of number of motor unit Summation of frequency Summation

47. Motor unit: one motor neuron plus the muscle fibers it innervates. Motor unit

49. Size Principle When a contraction occurs, small motor units fire first, as the strength of contraction increases, larger units are recruited, the orderly recruitment of motoneurons is referred to as size principle

50. Twitch and tetanus Twitch: mechanical response of muscle to single action potential. Tetanus: maintained mechanical response of muscle to high-frequency stimulation.  Incomplete tetanus  Complete tetanus

51. Twitch and tetanus

52. Neuromuscular transmission Excitation-contraction coupling Cross-bridge cycling Summary

53. Physiology Steps in the scientific method Homeostasis Regulation Nervous regulation: reflex Humoral regulation Autoregulation Control system Feedback control system: negative feedback; positive feedback Feed-forward control system

54. Summary Liquid mosaic model Simple diffusion Facilitated diffusion via carrier Facilitated diffusion through ion channel Voltage-gated ion channel Ligand-gated ion channel Mechanically-gated ion channel Primary active transport Secondary active transport Exocytosis and endocytosis

55. Summary Signal transduction mediated by  Chemically-gated ion channel  G-protein coupled receptor cAMP-PKA pathway IP3-Ca 2+ pathway DG-PKC pathway G protein-ion channel pathway  Enzyme coupled receptor

56. The end

57. Ultrastructure of smooth muscle Smooth muscle

58. Ultrastructure of smooth muscle Spindle-shaped cell with a diameter ranging from 2 to 10 μm Thin filament: thick filament=15:1 Dense body, dense area Intermediate filament

59. Two sources of Ca 2+ contribute to the rise in cytosolic Ca 2+ that initiates smooth muscle contraction Sarcoplasmic reticulum Extracellular Ca 2+ Molecular mechanisms of contraction

60. Single-unit smooth muscle (visceral smooth muscle): smooth muscle that responds to stimulation as single unit because gap junctions join fibers, allowing electrical activity to pass from cell to cell. Autorhythmicity Multi-unit smooth muscle: smooth muscle that exhibits little, if any, propagation of electrical activity from fiber to fiber and whose contractile activity is closely coupled to its neural input. Types of smooth muscle

61. Phasic contraction: rapid cyclic contraction and relaxation. Phasic smooth muscle Tonic contraction: smooth muscle can maintain a low level of active tension for long periods without cyclic contraction and relaxation. Tonic smooth muscle Modes of contraction

62. Autorhythmicity Varicosity Non-synaptic chemical transmission Innervation of smooth muscle End