PowerPoint Lecture Slides prepared by Janice Meeking, Mount Royal College CHAPTER 11 Muscle Synapses Mike Clark, M.D. Copyright 2010 Pearson Education, Inc. The Synapse A junction that mediates information transfer from one neuron: To another neuron, or to a gland or muscle cell Copyright 2010 Pearson Education, Inc.
The Synapse Presynaptic neuronconducts impulses toward the synapse Postsynaptic neurontransmits impulses away from the synapse PLAY Animation: Synapses Copyright 2010 Pearson Education, Inc. Muscle Synapses Neuromuscular junction Copyright 2010 Pearson Education, Inc. Chemical Synapses Specialized for the release and reception of neurotransmitters
Typically composed of two parts Axon terminal of the presynaptic neuron, which contains synaptic vesicles Receptor region on the postsynaptic membrane which in this case is a skeletal muscle cell Copyright 2010 Pearson Education, Inc. Events at the Neuromuscular Junction Skeletal muscles are stimulated by somatic motor neurons Axons of motor neurons travel from the central nervous system via nerves to skeletal muscles Each axon forms several branches as it enters a muscle Each axon ending forms a neuromuscular junction with a single muscle fiber
Copyright 2010 Pearson Education, Inc. Synaptic Cleft Fluid-filled space separating the presynaptic and postsynaptic neurons Prevents nerve impulses from directly passing from one neuron to the next Copyright 2010 Pearson Education, Inc. Action potential (AP) Myelinated axon of motor neuron Axon terminal of neuromuscular junction Nucleus
Sarcolemma of the muscle fiber 1 Action potential arrives at axon terminal of motor neuron. 2 Voltage-gated Ca2+ channels open and Ca2+ enters the axon terminal. Ca2+ Ca2+ Axon terminal of motor neuron Synaptic vesicle containing ACh Mitochondrion
Synaptic cleft Fusing synaptic vesicles Copyright 2010 Pearson Education, Inc. Figure 9.8 Neuromuscular Junction Situated midway along the length of a muscle fiber Axon terminal and muscle fiber are separated by a gel-filled space called the synaptic cleft Synaptic vesicles of axon terminal contain the neurotransmitter acetylcholine (ACh) Junctional folds of the sarcolemma contain ACh receptors
Copyright 2010 Pearson Education, Inc. Action potential (AP) Myelinated axon of motor neuron Axon terminal of neuromuscular junction Nucleus Sarcolemma of the muscle fiber 1 Action potential arrives at axon terminal of motor neuron. 2 Voltage-gated Ca2+ channels open and Ca2+ enters the axon
terminal. Ca2+ Ca2+ Axon terminal of motor neuron Synaptic vesicle containing ACh Mitochondrion Synaptic cleft Fusing synaptic vesicles Copyright 2010 Pearson Education, Inc.
Figure 9.8 Copyright 2010 Pearson Education, Inc. Copyright 2010 Pearson Education, Inc. Synaptic Cleft Transmission across the synaptic cleft: Is a chemical event (as opposed to an electrical one) Involves release, diffusion, and binding of neurotransmitters Ensures unidirectional communication between neurons PLAY Animation: Neurotransmitters Copyright 2010 Pearson Education, Inc.
Information Transfer AP arrives at axon terminal of the presynaptic neuron and opens voltage-gated Ca2+ channels Synaptotagmin protein binds Ca2+ and promotes fusion of synaptic vesicles with axon membrane Exocytosis of neurotransmitter occurs Copyright 2010 Pearson Education, Inc. Events at the Neuromuscular Junction Nerve impulse arrives at axon terminal ACh is released and binds with receptors on the sarcolemma Electrical events lead to the generation of an action potential Copyright 2010 Pearson Education, Inc.
Information Transfer Neurotransmitter diffuses and binds to receptors (often chemically gated ion channels) on the postsynaptic membrane Ion channels are opened, causing a motor end plate potential on the skeletal muscle cell membrane Copyright 2010 Pearson Education, Inc. Synaptic Delay Neurotransmitter must be released, diffuse across the synapse, and bind to receptors Synaptic delaytime needed to do this (0.3 5.0 ms) Synaptic delay is the rate-limiting step of neural transmission Copyright 2010 Pearson Education, Inc.
Motor End Plate Potentials Neurotransmitter binds to and opens chemically gated channels that allow simultaneous flow of Na+ and K+ in opposite directions (Calcium ions also move into the Cell membrane) but Chloride does not exit in that the membrane blocks it. Na+ influx is greater that K+ efflux, causing a net depolarization Copyright 2010 Pearson Education, Inc. Chemical Classes of Neurotransmitters Acetylcholine (Ach) Released at neuromuscular junctions and some ANS neurons Synthesized by enzyme choline acetyltransferase Degraded by the enzyme acetylcholinesterase
(AChE) Copyright 2010 Pearson Education, Inc. Destruction of Acetylcholine ACh effects are quickly terminated by the enzyme acetylcholinesterase Prevents continued muscle fiber contraction in the absence of additional stimulation Copyright 2010 Pearson Education, Inc. Myelinated axon of motor neuron Axon terminal of neuromuscular junction Sarcolemma of the muscle fiber
Action potential (AP) Nucleus 1 Action potential arrives at axon terminal of motor neuron. 2 Voltage-gated Ca channels 2+ Ca2+ Ca2+ open and Ca2+ enters the axon terminal. Axon terminal of motor neuron 3 Ca2+ entry causes some
synaptic vesicles to release their contents (acetylcholine) by exocytosis. Fusing synaptic vesicles ACh 4 Acetylcholine, a neurotransmitter, diffuses across the synaptic cleft and binds to receptors in the sarcolemma. Na+ K+ channels that allow simultaneous passage of Na+ into the muscle fiber and K+ out of the muscle
fiber. by its enzymatic breakdown in the synaptic cleft by acetylcholinesterase. Copyright 2010 Pearson Education, Inc. Junctional folds of sarcolemma Sarcoplasm of muscle fiber 5 ACh binding opens ion 6 ACh effects are terminated Synaptic vesicle containing ACh Mitochondrion
Synaptic cleft Ach Degraded ACh Na+ Acetylcholinesterase Postsynaptic membrane ion channel opens; ions pass. Postsynaptic membrane ion channel closed; ions cannot pass. K+
Figure 9.8 Events in Generation of an Action Potential 1. Local depolarization (end plate potential): ACh binding opens chemically (ligand) gated ion channels Simultaneous diffusion of Na+ (inward) and K+ (outward) More Na+ diffuses, so the interior of the sarcolemma becomes less negative
Local depolarization end plate potential Copyright 2010 Pearson Education, Inc. Events in Generation of an Action Potential 2. Generation and propagation of an action potential: End plate potential spreads to adjacent membrane areas Voltage-gated Na+ channels open Na+ influx decreases the membrane voltage
toward a critical threshold If threshold is reached, an action potential is generated Copyright 2010 Pearson Education, Inc. Events in Generation of an Action Potential Local depolarization wave continues to spread, changing the permeability of the sarcolemma Voltage-regulated Na+ channels open in the adjacent patch, causing it to depolarize to threshold Copyright 2010 Pearson Education, Inc. Events in Generation of an Action Potential
3. Repolarization: Na+ channels close and voltage-gated K+ channels open K+ efflux rapidly restores the resting polarity Fiber cannot be stimulated and is in a refractory period until repolarization is complete Ionic conditions of the resting state are restored by the Na+-K+ pump
Copyright 2010 Pearson Education, Inc. Copyright 2010 Pearson Education, Inc. Copyright 2010 Pearson Education, Inc. Axon terminal Open Na+ Channel Na+ Synaptic cleft ACh tio n l ar iza
of de po ACh Na+ K+ Na+ K+ e Wa v 1 Local depolarization: generation of the end plate potential on the sarcolemma ++
++ + + Closed K+ Channel K+ Action potential + + +++ + 2 Generation and propagation of the action potential (AP) Closed Na+ Open K+ Channel Channel Na+
K+ Sarcoplasm of muscle fiber Copyright 2010 Pearson Education, Inc. 3 Repolarization Figure 9.9 Axon terminal Open Na+ Channel Na+ Synaptic cleft ACh K tio n
++ ++ + + K+ Action potential + + +++ + iza Na + of d
ep o l ar ACh Na+ K+ + Closed K+ Channel ve Wa 11 Local depolarization: generation of the end plate potential on the sarcolemma
Sarcoplasm of muscle fiber Copyright 2010 Pearson Education, Inc. Figure 9.9, step 1 Axon terminal Open Na+ Channel Na+ Synaptic cleft ACh K tio n iza
Na + K+ ++ ++ + + Action potential + + +++ + 2 Generation and propagation of the action potential (AP) of
d ep o l ar ACh Na+ K+ + Closed K+ Channel ve Wa 11 Local depolarization: generation of the
end plate potential on the sarcolemma Sarcoplasm of muscle fiber Copyright 2010 Pearson Education, Inc. Figure 9.9, step 2 Closed Na+ Channel Open K+ Channel Na+ K+ 3 Repolarization Copyright 2010 Pearson Education, Inc.
Figure 9.9, step 3 Axon terminal Open Na+ Channel Na+ Synaptic cleft ACh tio n l ar iza ++ ++ + + K+
Action potential + + +++ + 2 Generation and propagation of the action potential (AP) of de po ACh Na+ K+ Na+ K+ Closed K+
Channel e Wa v 1 Local depolarization: generation of the end plate potential on the sarcolemma Closed Na+ Open K+ Channel Channel Na+ K+ Sarcoplasm of muscle fiber
Copyright 2010 Pearson Education, Inc. 3 Repolarization Figure 9.9 Depolarization due to Na+ entry Na+ channels close, K+ channels open Repolarization due to K+ exit Na+ channels open Threshold K+ channels
close Copyright 2010 Pearson Education, Inc. Figure 9.10 Excitation-Contraction (E-C) Coupling Sequence of events by which transmission of an AP along the sarcolemma leads to sliding of the myofilaments Latent period: Time when E-C coupling events occur Time between AP initiation and the beginning of contraction Copyright 2010 Pearson Education, Inc. Blockade Muscle Relaxants Neuromuscular-blocking drugs block neuromuscular transmission at the
neuromuscular junction,causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine (ACh) synthesis or release, or by acting postsynaptically at the acetylcholine receptor. While there are drugs that act presynaptically (such as botulin toxin and tetrodotoxin), the clinically-relevant drugs work postsynaptically. Copyright 2010 Pearson Education, Inc. Clinically, neuromuscular block is used as an adjunct to anesthesia to induce paralysis, so that surgery, especially intra-abdominal and intra-thoracic surgeries, can be carried out with fewer complications. Because neuromuscular block may paralyze muscles required for breathing, mechanical ventilation should be available to maintain adequate respiration.
Copyright 2010 Pearson Education, Inc. These drugs fall into two groups: Non-depolarizing blocking agents: These agents constitute the majority of the clinicallyrelevant neuromuscular blockers. They act by blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors.[2] Depolarizing blocking agents: These agents act by depolarizing the plasma membrane of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh. Copyright 2010 Pearson Education, Inc. Non-depolarizing blocking agents Below are some of the more common agents that act as competitive antagonists against acetylcholine at the site of postsynaptic acetylcholine receptors.
Tubocurarine, found in curare of the South American plant genus Strychnos, is the prototypical nondepolarizing neuromuscular blocker. It has a slow onset (>5 min) and a long duration of action (12 hours). Side effects include hypotension, which is partially explained by its effect of increasing histamine release, a vasodilator,[3] as well as its effect of blocking autonomic ganglia.[4] It is excreted in the urine. Copyright 2010 Pearson Education, Inc. Depolarizing blocking agents Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and
only transiently depolarizes the muscle. Copyright 2010 Pearson Education, Inc. The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of action (510 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood). Succinylcholine was originally known as diacetylcholine because structurally it is composed of two acetylcholine molecules joined with a methyl group. Decamethonium is sometimes, but rarely, used in clinical practice. Inhibition of acetylcholinesterase may be used to cause the same effect as a depolarizing neuromuscular block. Copyright 2010 Pearson Education, Inc.
Comparison of drugs The main difference is in the reversal of these two types of neuromuscular-blocking drugs. Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs since they are competitive antagonists at the ACh receptor so can be reversed by increases in ACh. The depolarizing blockers already have ACh-like actions, so these agents will have prolonged effect under the influence of acetylcholinesterase inhibitors. The administration of depolarizing blockers will initially exhibit fasciculations (a sudden twitch just before paralysis occurs). This is due to the depolarization of the muscle. Also, post-operative pain is associated with depolarizing blockers. The tetanic fade is the failure of muscles to maintain a fused tetany at sufficiently-high frequencies of electrical stimulation. Non-depolarizing blockers will have this effect on patients. Depolarizing blockers will not. Copyright 2010 Pearson Education, Inc.
