Neuromuscular transmission

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Steps Of Neuromuscular Transmission, Synapse, Neuro-Muscular Junction, Quantal Release, Acetyl Choline Receptor Physiology

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  • neuro4e-fig-08-11-0.jpg
  • Cholinesterase provides for a very rapid mechanism of inactivation. This makes acetylcholine a preferred transmitter where rapid modulation of the signal is desired. Example: Voluntary muscular action.
  • ACh: acetylcholine
    AChR: acetylcholine receptor is the nicotinic hetero(and penta)meric muscle form, which has (1)2,,, fetal subunit composition and (1)2,,, adult subunit composition
  • Endplate potentials (EPPs) are larger, compound MEPPs that result from the activation of many of the terminals of an endplate at the same time. The average EPPs results from the summation of ~150 average MEPPs. The average EPP amplitude is therefore ~+60 mV (0.4 mV/quantum X 150 quanta). If the resting VM of the muscle fiber is -90 mV and the threshold for action potential initiation is -50 mV, a single average EPP will provide 1.5X the voltage required to change VM to the action potential threshold! The normal “safety factor” for neuromuscular excitation is therefore quite high, ~2. That means that under normal circumstances, a muscle action potential will always be generated, and the muscle will contract, as a result of a single EPP. If the fiber is repeatedly stimulated over a very long period of time, some failures will be observed, because the axon will start to run out of vesicles and/or the muscle will fatigue.
  • Neuromuscular transmission

    1. 1. Anatomy Critical to function
    2. 2. NMJ on the muscle fiber 10µm 10µm
    3. 3. Synaptic selectivity at developing NMJ
    4. 4. Synapse from a frog sartorius neuromuscular junction showing vesicles clustered in the active zone, some docked at the membrane (arrows). (from Heuser, 1977)
    5. 5. Synaptic Transmission The Steps
    6. 6. Synaptic Transmission Model • • • • • • Precursor transport NT synthesis Storage Release Activation Termination ~diffusion, degradation, uptake, autoreceptors
    7. 7. Presynaptic Axon Terminal Terminal Button Postsynaptic Membrane
    8. 8. (1) Precursor Transport
    9. 9. (2) Synthesis _ _ _ enzymes/cofactors NT
    10. 10. (3) Storage in vesicles
    11. 11. A quantum is the number of transmitters released from a single synaptic vesicle Vesicles have a fairly uniform size and diameter ≈ 40- 50 nm Individual vesicles contain 8000 - 10,000 phospholipid molecules and several proteins. The vesicle molecular weight is approx. 3-5 x 106
    12. 12. Proteins associated with synaptic vesicles (identified through sequencing and cloning of cDNA’s) Membrane proteins A. B. C. Synaptophysin (~ 36 kD) Synaptotagmin (~ 61 kD; the Ca2+ sensor) Snares (residents of either the vesicle [v-snare] or the target membrane [t-snare]) 1. VAMP (also called synaptobrevin), a v-snare (~18 kD) 2. Syntaxin, a t-snare that also associates with Ca 2+ channels (~32 kD; technically not a vesicle protein) 3. SNAP-25, a t-snare (~25 kD; also technically not a vesicle protein) D. Electrogenic proton ATPase -creates emf that drives neurotransmitter uptake against a concentration gradient
    13. 13. Proteins associated with synaptic vesicles (identified through sequencing and cloning of cDNA’s) Membrane proteins A. B. C. Synaptophysin (~ 36 kD) Synaptotagmin (~ 61 kD; the Ca2+ sensor) Snares (residents of either the vesicle [v-snare] or the target membrane [t-snare]) 1. VAMP (also called synaptobrevin), a v-snare (~18 kD) 2. Syntaxin, a t-snare that also associates with Ca 2+ channels (~32 kD; technically not a vesicle protein) 3. SNAP-25, a t-snare (~25 kD; also technically not a vesicle protein) D. Electrogenic proton ATPase -creates emf that drives neurotransmitter uptake against a concentration gradient
    14. 14. An alternative form of Ca2+-dependent vesicle fusion, termed fast tracking, or “kiss and run” predominates at low frequency stimulation.
    15. 15. Life cycle of a synaptic vesicle
    16. 16. Terminal Button Dendritic Spine Synapse
    17. 17. (4) Release Terminal Button Dendritic Spine Synapse Receptors
    18. 18. Terminal Button AP Dendritic Spine Synapse
    19. 19. Exocytosis Ca2+
    20. 20. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm
    21. 21. Stimulation mini Evoked amplitudes. 1X 4X Mini histogram. 2X 1X 3X 4X 2X 1 mV Squire Fund. Neurosci.
    22. 22. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm
    23. 23. “docked” No firing “fast” “slow” Firing Heuser and Reese, 1981 Electron micrographs of “omega figures” (fusing synaptic vesicles) after slam freezing a firing synapse provided clinching evidence for the vesicle hypothesis.
    24. 24. A cholinergic synapse Ne rv Action potential Choline ef ibe r( ax on ) Na+, Cl- Acetyl-CoA Acetyl-Choline Ca + + Ca + + Acetyl-Choline
    25. 25. A cholinergic synapse (2): Rapid transmitter inactivation by cholinesterase Choline Acetate Action potential Acetyl-CoA Acetyl-Choline Ca + + Choline esterase
    26. 26. (5) Activation
    27. 27. (1) Ionotropic Channels Channel NT neurotransmitter
    28. 28. Ionotropic Channels NT Pore
    29. 29. Ionotropic Channels NT
    30. 30. Ionotropic Channels NT
    31. 31. Acetylcholine Receptor α β γ (or ε) ACh ACh δ α Miyazawa, A., Y. Fujiyoshi, and N. Unwin. 2003. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423:949-955.
    32. 32. End Plate Potential (EPP) Presynaptic terminal VNa Muscle Membrane Voltage (mV) The movement of Na+ and K+ depolarizes muscle membrane potential (EPP) 0 EPP Threshold -90 mV VK Presynaptic AP Time (msec) Outside Muscle membrane Inside ACh Receptor Channels Voltage-gated Na Channels Inward Rectifier K Channels 45
    33. 33. Normal EPPs invariably evoke muscle action potentials • Normally, the average EPP amplitude = 60 mV -In frog, ~150 vesicles • Safety factor for transmission is therefore high (greater than 1) - Frog example: ∆VEPP ÷ ∆VAPthreshold = 60 mV ÷ │-90 mV*- [-50 mV] │ = 60 mV ÷ 40 mV = 1.5 (*muscle resting VM = -90 mV)
    34. 34. (6) Termination
    35. 35. (6.1) Termination by... Diffusion
    36. 36. (6.2) Termination by... Enzymatic degradation
    37. 37. Acetylcholine Metabolism acetylcholine ACh esterase (AChE) choline + acetate • AChE is located in the synaptic cleft • Choline is taken back up into the presynaptic terminal – active process • Acetate diffuses away to be utilized in other metabolic roles
    38. 38. (6.3) Termination by... Reuptake
    39. 39. (6.4) Termination by... Autoreceptors A
    40. 40. The Safety Factor !!! • Number of Quanta • The receptor density on the post synaptic membrane • The activity of ACH esterase • The folds of the PS membrabe • The presence of active zones
    41. 41. Voltage-gated channels
    42. 42. Na+ channelopathies Gene Channel Disease Muscle SCN4A α subunit of NaV1.4 Hyperkalaemic periodic paralysis Hypokalaemic periodic paralysis Paramyotonia congenita Potassium-aggravated myotonia Myotonia fluctuans Myotonia permanens etc Neuronal SCN1A α subunit of NaV1.1 (somatic) Generalised Epilepsy with Febrile Seizures + (GEFS+), Severe myoclonic epilepsy of infancy (SMEI) SCN2A α subunit of NaV1.2 (axonal) GEFS+ SCN1B β1 subunit
    43. 43. Ca2+ channel structure α2δ γ β α1
    44. 44. Ca2+ channelopathies Gene Neuronal Disease CACNA1S α subunit of CaV1.1 HypoK periodic paralysis Malignant hyperthermia RYR1 Muscle Channel Ryanodine receptor (sarcoplasmic channel) Malignant hyperthermia Central core disease CACNA1A α subunit of CaV2.1 (P/Q-type channel) Familial hemiplegic migraine Episodic ataxia type 2 Spinocerebellar ataxia type 6 Absence epilepsy? CACNA1H αsubunit of CaV3.2 (T-type channel) Absence epilepsy
    45. 45. Nicotinic receptor channelopathies Gene CHRNA1 α1 subunit Congenital myasthenic syndrome β1 subunit CHRND δ subunit CHRNE Neuronal Disease CHRNB1 Muscle Channel ε subunit CHRNA2 α4 subunit CHRNB4 β2 subunit AD nocturnal frontal lobe epilepsy
    46. 46. Slow channel syndrome Sine et al (1995)
    47. 47. Fast channel syndrome can be associated with congenital joint deformities (arthrogryposis multiplex) Brownlow et al (2001)

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