Figure 1119

Events at a neuromuscular junction that lead to an action potential in the muscle-fiber plasma membrane. ^

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Muscle CHAPTER ELEVEN

Muscle CHAPTER ELEVEN

TABLE 11-2 Sequence of Events Between a Motor Neuron Action Potential and Skeletal-Muscle Fiber Contraction

1. Action potential is initiated and propagates in motor neuron axon.

2. Action potential triggers release of ACh from axon terminals at neuromuscular junction.

3. ACh diffuses from axon terminals to motor end plate in muscle fiber.

4. ACh binds to receptors on motor end plate, opening Na+, K+ ion channels.

5. More Na+ moves into the fiber at the motor end plate than K+ moves out, depolarizing the membrane, producing the endplate potential (EPP).

6. Local currents depolarize the adjacent plasma membrane to its threshold potential, generating an action potential that propagates over the muscle fiber surface and into the fiber along the transverse tubules.

7. Action potential in transverse tubules triggers release of Ca2+ from lateral sacs of sarcoplasmic reticulum.

8. Ca2+ binds to troponin on the thin filaments, causing tropomyosin to move away from its blocking position, thereby uncovering cross-bridge binding sites on actin.

9. Energized myosin cross bridges on the thick filaments bind to actin:

A + M* • ADP • Pj -> A • M* • ADP • Pi

10. Cross-bridge binding triggers release of the strained conformational state of myosin, producing an angular movement of each cross bridge:

11. ATP binds to myosin, breaking linkage between actin and myosin and thereby allowing cross bridges to dissociate from actin:

12. ATP bound to myosin is split, energizing the myosin cross bridge:

13. Cross bridges repeat steps 9 to 12, producing movement of thin filaments past thick filaments. Cycles of cross-bridge movement continue as long as Ca2+ remains bound to troponin.

14. Cytosolic Ca2+ concentration decreases as Ca2+ is actively transported into sarcoplasmic reticulum by Ca-ATPase.

15. Removal of Ca2+ from troponin restores blocking action of tropomyosin, the cross-bridge cycle ceases, and the muscle fiber relaxes.

postsynaptic potentials) are produced. They hyperpolar-ize or stabilize the postsynaptic membrane and decrease the probability of its firing an action potential. In contrast, inhibitory potentials do not occur in human skeletal muscle; all neuromuscular junctions are excitatory.

In addition to receptors for ACh, the surface of the motor end plate contains the enzyme acetylcholinesterase, which breaks down ACh, just as occurs at ACh-mediated synapses in the nervous system. ACh bound to receptors is in equilibrium with free ACh in the cleft between the nerve and muscle membranes. As the concentration of free ACh falls because of its breakdown by acetylcholinesterase, less ACh is available to bind to the receptors. When the receptors no longer contain bound ACh, the ion channels in the end plate close. The depolarized end plate returns to its resting potential and can respond to the subsequent arrival of ACh released by another nerve action potential.

Table 11-2 summarizes the sequence of events that lead from an action potential in a motor neuron to the contraction and relaxation of a skeletal-muscle fiber.

There are many ways by which events at the neu-romuscular junction can be modified by disease or drugs. For example, the deadly South American arrowhead poison curare binds strongly to the ACh receptors, but it does not open their ion channels and is not destroyed by acetylcholinesterase. When a receptor is occupied by curare, ACh cannot bind to the receptor. Therefore, although the motor nerves still conduct normal action potentials and release ACh, there is no resulting EPP in the motor end plate and hence no contraction. Since the skeletal muscles responsible for breathing, like all skeletal muscles, depend upon neuromuscular transmission to initiate their contraction, curare poisoning can lead to death by asphyxiation. Drugs similar to curare are used in small amounts to prevent muscular contractions during certain types of surgical procedures when it is necessary to immobilize the surgical field. Patients are artificially ventilated in order to maintain respiration until the drug has been removed from the system.

PART TWO Biological Control Systems

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

Neuromuscular transmission can also be blocked by inhibiting acetylcholinesterase. Some organophos-phates, which are the main ingredients in certain pesticides and "nerve gases" (the latter developed for biological warfare), inhibit this enzyme. In the presence of such agents, ACh is released normally upon the arrival of an action potential at the axon terminal and binds to the end-plate receptors. The ACh is not destroyed, however, because the acetylcholinesterase is inhibited. The ion channels in the end plate therefore remain open, producing a maintained depolarization of the end plate and the muscle plasma membrane adjacent to the end plate. A skeletal-muscle membrane maintained in a depolarized state cannot generate action potentials because the voltage-gated sodium channels in the membrane have entered an inactive state, which requires repolarization to remove. Thus, the muscle does not contract in response to subsequent nerve stimulation, and the result is skeletal-muscle paralysis and death from asphyxiation.

A third group of substances, including the toxin produced by the bacterium Clostridium botulinum, blocks the release of acetylcholine from nerve terminals. Botulinum toxin is an enzyme that breaks down a protein required for the binding and fusion of ACh vesicles with the plasma membrane of the axon terminal. This toxin, which produces the food poisoning called botulism, is one of the most potent poisons known because of the very small amount necessary to produce an effect.

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