Neuromuscular Transmission

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  • 1. Neuromuscular Transmission – sequence of events, neuromuscular blockers, their mechanism and clinical importance
  • 2. Neuromuscular Junctions: • The synapse between the axons of motorneurons and skeletal muscle fibers are called neuromuscular junction. • The NMJ was the first vertebrate synapse to be well characterized. • NMJ serves as a model chemical synapse that provides a basis for understanding more complex synaptic interactions among neurons in the centeral nerrvous system.
  • 3. • The skeletal muscle fibers are innervated by myelinated nerve fibers . Each motor nerve fiber branches, after entering the muscle and stimulates 3 to few hundred muscle fibers.
  • 4. Motor Unit: • Each single motor neuron and the muscle fibers it innervates constitute a motor unit. • In muscles such as those of the hand and those concerned with motion of the eye (i.e, muscles concerned with fine, graded, precise movement), each motor unit innervates 3 to 6 muscle fibers. • 120 – 165 fibers per unit have been reported in the large muscles of the back.
  • 5. Structure of NMJ: • Near the NMJ the motor nerve loses its myelin sheath and divides into terminal branches. • The terminal branches of the axon lie in SYNAPTIC TROUGHS on the surface of the muscle cells. • The plasma membrane of the muscle cell lining the TROUGH is thrown into numerous juntional folds called SUB NEURAL CLEFTS ( which increases the surface area for the action of neurotransmitter).
  • 6. Structure of NMJ: 1. PRE SYNAPTIC NEURON – AXON TERMINAL: • Has many mitochondria which supply ATP, the source of energy for the synthesis of Ach. Ach is stored in the synaptic vesicles present in the terminals. About 3 lakh vesicles are present in the terminals of a single motor end plate. • On inside surface of the membrane of axon terminal are DENSE BAR. On each side of dense bar is voltage gated calcium channels.
  • 7. Structure of NMJ: 2. POST SYNAPTIC MEMBRANE – PLASMA MEMBRANE OF MUSCLE: • Has Ach receptor which are Ach-gated channels located near the mouths of sub-neural clefts. These channels lie immediately below the dense bars, so that the Ach released can easily enter these channels. These channel remain close until 2 Ach molecules attach to them. This causes conformational change that open the channel.
  • 8. NMT – Sequence of Events: Arrival of action potential in presynaptic motor axon terminals Opening of voltage-gated Ca2+ channels of axon terminals and influx of Ca2+ from synaptic space into axon terminal Synaptic vesicle fuse with the membrane and empty Ach into synaptic cleft by exocytosis. Ca ++ attract the synaptic vesicles toward release sites on the presynaptic membrane adjacent to Dense bars. Two molecules of Ach bind with Ach receptors (Ach gated ion channels)
  • 9. Development of End – plate potential Contraction of muscle fiber Increase in permeability of postjunctional membrane to Na+ causes influx of Na+ Development of Action Potential Spreading of action potential along muscle membrane Conformational change and opening of Ach channels
  • 10. (Active zone) influx of Ca 2+ thru voltage gated channels of ACh Each vesicle has about 10,000 molecules of Ach.
  • 11. + 50mv
  • 12. EPP: : localized Nonpropagated. RMP - 90mv. Has voltage gated channels + 50- 75 mV
  • 13. End Plate potential Depolarization of presynaptic nerve membrane causes influx of Ca++ . 4 Ca2+ ions are needed to bind ACh containing vesicles with the presynaptic membrane at the active zones and causes exocytosis and release of ACh in the synaptic cleft. Binding of ACh with the ACh receptors in the post synaptic membrane of the motor end plate causes opening of ligand gated Na+ & K+ channels which cause greater influx of Na+ than efflux of K+ leading to localized depolarization of motor end plate to about + 50-75mv called as the End Plate Potential.
  • 14. Generation of Muscle Action Potential This localized depolarization EPP [+ 50 to 75 mV] in itself is non propagated but causes flow of current between EPP and adjacent sarcolemma which has voltage gated channels. When the depolarization at this region reaches threshold, it leads to generation of muscle action potential. This muscle action potential is then conducted through out the sarcolemma on either side and T tubules of the whole of muscle fiber which initiates muscle contraction.
  • 15. Miniature End Plate Potentials- MEPP These potentials are generated at the motor end plate in resting state due to random fusion of ACh containing vesicles in the presynaptic neural terminal leading to release of ACh in the synaptic cleft. This ACh diffuses to motor end plate and causes localized depolarization of the motor end plate of about 0. 5mV.
  • 16. Nicotinic AChR
  • 17. Myasthenia Gravis
  • 18. Normal Acetylcholine Receptors Life span of ACh receptor is 10 days Are protein in nature Constant synthesis ACh receptors get incorporated into muscle membrane only at motor end plate in innervated muscle Old ACh receptors get internalized by endocytosis and then degraded by lysosome activity
  • 19. In Myasthenia Gravis There are circulating antibodies(IgG) against ACh receptors. IgG causes  Aggregation & Clustering of ACh receptors  Endocytosis and degradation of clusters  Rate of destruction greater than the rate of formation Destroys post synaptic membrane also which leads to  Less availability of membrane surface area at NMJ for incorporation of ACh receptors  Widening of synaptic clefts  Sparse and shallow folds
  • 20.  decrease the amount of ACh released from presynaptic terminal.  affect the rate of synthesis of ACh receptors  affect incorporation of receptors into muscle membrane  produce abnormal receptors  block the interaction between ACh and ACh-R In myasthenia gravis ACh receptor antibodies DO NOT
  • 21. In myasthenia gravis ACh released acts normally on ACh receptors and produces end plate potential but its magnitude is decreased due to decrease in the total number of receptors and widening of synaptic cleft. This decreased amplitude of EPP fails to generate muscle action potential, so failure of muscle contraction
  • 22. Sequence of Events in Myasthenia Gravis ( Only skeletal muscles are affected) ↓ in ACh receptors ↓ ↓ number of interaction between ACh and ACh-R ↓ number of opening of Na+ channels ↓ amplitude of E.P.P. Failure of generation of muscle action potential No contraction of muscle ↓ Weakness of muscle
  • 23. Blockers of ACh Receptor Sites which lead to muscle weakness or paralysis  Auto-immune antibodies in Myasthenia Gravis destroy ACh receptors  Curare binds with ACh receptors  Some muscle relaxant drugs
  • 24. Diseases and chemical agents that affect the neuromuscular junction Blocks release of ACh Clostridium botulinum toxin (food poisoning) Blocks Ca++ channels Lambert-Eaton in presynaptic terminal Syndrome Causes explosive Black widow spider release of Ach venom Alters Release of Ach Chemical Agent or Disease
  • 25. Prevents Inactivation of Ach Irreversibly inhibits ACh-estrase Organophosphates in nerve gas & pesticides Blocks the action of ACh-estrase, thus prolongs the actionof ACh. Neostigmine [ used in myasthenia gravis]