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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
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Chapter 2 Basic Functions of cells 谢俊霞 教授
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Striated muscle Skeletal muscle Cardiac muscle Smooth muscle Striated muscle
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Anatomy of neuromuscular junction Sequence of events during transmission Characteristics of end-plate potential Factors affecting neuromuscular transmission Neuromuscular transmission
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Anatomy of neuromuscular junction
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Prejunctional membrane Synaptic vesicle Active zone Junctional cleft Endplate membrane Junctional fold N 2 -Ach receptor cation channel Acetylcholinesterase Anatomy of neuromuscular junction
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Sequence of events during transmission
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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
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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
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Characteristics of end- plate potential
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Sequence of events during transmission
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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
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B1 Transmitter-gated and voltage- gated channels are in parallel B2 Effect of transmitter-gated channels on voltage-gated channels
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Miniature end-plate potential
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Quantal release
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Summary - Neurotransmission
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Nicotinic acetylcholine receptor cation channel
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Factors affecting neuromuscular transmission Ca 2+ concentration at presynaptic terminal: Ca 2+ chelate Activity of ACh receptor: tubocurarine; α-bungarotoxin Acetylcholinesterase (AChE) inhibitor: pyridostigmine
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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.
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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
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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)
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Myofibril and sarcomere Ultrastructure of striated muscle
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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
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Myofilament sliding theory: process of muscle contraction in which shortening occurs by thick and thin filaments sliding past each other. Molecular mechanisms of contraction
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Molecular components of myofilament
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Process of muscle contraction Cross-bridge cycling
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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?
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Excitation-contraction coupling: mechanism in muscle fibers linking plasma-membrane depolarization with cross- bridge force generation. Excitation-contraction coupling
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Intracellular Ca 2+ is the key of excitation-contraction coupling Excitation-contraction coupling
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Difference of Ca 2+ release between skeletal and cardiac muscle Calcium-induced Ca 2+ release, CICR
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Time relationships between action potential and the resulting shortening and relaxation of the muscle fiber
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Time relationships between action potential, intracellular [Ca 2+ ] and twitch tension Calcium transient
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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
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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
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Isometric contraction and isotonic contraction Isometric twitch Isotonic twitch Latent period Tension Distance shortened
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Preload Optimal initial length: the length at which the fiber develops the greatest tension.
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Afterload
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Intracellular Ca 2+ level ATPase activity of myosin Contractility
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Summation of number of motor unit Summation of frequency Summation
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Motor unit: one motor neuron plus the muscle fibers it innervates. Motor unit
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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
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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
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Twitch and tetanus
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Neuromuscular transmission Excitation-contraction coupling Cross-bridge cycling Summary
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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
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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
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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
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The end
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Ultrastructure of smooth muscle Smooth muscle
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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
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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
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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
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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
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Autorhythmicity Varicosity Non-synaptic chemical transmission Innervation of smooth muscle End
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