topic 3

• Acetylcholine (ACh)


  • Non-peptide transmitter - synthesised in the terminal while vesicle is transported from cell body to terminal
  • Acetyl-Coenzyme A (AcCoA) - produced in mitochondria and released into cytoplasm
  • Choline is a vitamin-like essential nutrient
  • AcCoA and Choline combine, releasing CoA and ACh is stored in the vesicle
  • ACh is released into the cleft and broken down to release choline
  • Choline is recycled using an Na+ exchange pump back into the terminal, acetate is broken down
• Vesicle priming and docking


  Required as Ca2+ entry (via voltage-gated channels) is brief
• Acetylcholine receptors

  • Nicotinic acetylcholine receptors (nAChR)
  • Muscarinic acetylcholine receptors (mAChR)
• Muscarinic acetylcholine receptors (mAChR)


  • Made of polypeptides (G-protein linked - metabotropic receptors)
  • No central pore, more steps so slower effects
  • At cardiac and smooth muscles
• End Plate-Potential (EPP)

  • ACh induces a depolarising post-synaptic membrane potential change
  • Na+ and Ca+ enter the cell, K+ exits therefore gaining positive charge
  • RMP for skeletal muscle = -80 mV (muscles are less leaky)
  • Large depolarisation up to -20 mV, EPP
  • EPP flows away electrotonically, just adjacent to the endplate muscles can produce AP (voltage-gated Ca2+ channels on muscle)
  • Size of EPP based on amount of ACh bound to AChR
  • Ca2+ channels are not refractory, which allows for a slower repolarisation
• Safety Margin


  • Trough design of NMJ --> ensures transmitters will not immediately diffuse away
  • Each vesicle has 6,000 - 10,000 ACh molecules
  • Vesicles are pre-docked + there are as many as 300 active zones on each axon terminal at the NMJ --> ~500,000 vesicles at active zones
  • Junction folds provide large SA to concentrate AChR
  • AChR binds to ACh for 1 ms - longer than most transmitters & keeps ACh concentration gradient
  • Only 10% of receptors needed to generate AP (large redundancy)
  • EPP is around 40 mV, more than enough for post-synaptic AP generation
• Toxins affecting NMJ transmission

  • ACh release inhibitors - botulum toxin (breaks down SNAP25 protein needed for vesicles to anchor to cell membrane, thus vesicles cannot fuse, thus no ACh release, thus muscle paralysis & prevents wrinkles)
  • AChR inhibitors - muscle AChR blocked by South American poison (curare)
  • AChE inhibitors - plant poison, physostigmine, nerve gases and organophosphorus pesticides
  • Transmitter vesicle depletors - black widow spider toxin, alpha-latroxin
• Myasthenia Gravis


  • Acquired autoimmune disease that causes intense fatigue, body produces antibodies against AChR
  • They bind to AChR so ACh cannot bind
  • Crosslink receptors which are then drawn into clusters and rapidly endocytosed by body, so less receptors
  • Decreases folds & widens synaptic cleft
• Signalling between Neurons

  • Divergent signalling (each neuron outputs to many neurons)
  • Convergent signalling (each neuron receives many inputs)
  • Excitatory or inhibitory responses
  • Can be fast or slow/ long-term
• Post-synaptic Potentials

  • Excitatory (EPSP) --> less negative, towards threshold
  • Inhibitory (IPSP) --> more negative, suppresses target neuron
  • PSP's can sum (add up smaller APs) and create a bigger PSP
  • Refractory period has occurred in the pre-synaptic neuron, summation happens in post-synaptic neuron
• Neuron to neuron transmission is less efficient than neuron to skeletal muscle transmission: requires more analysis (not just a 1 input: 1 output system), involves integration & decision making
• Control pre-synaptic input

  1. Inhibit amount of transmitter released

  2. Reduction of terminal depolarisation/vesicle release/ no. of transmitter binding

  3. Pre-synaptic inhibition --> Activation of inhibitory neuron that blocks the excitatory neuron's terminal

  4. Post-synaptic inhibition --> block target neuron to prevent response entirely

  5. Facilitatory neuron --> increases excitatory neuron's response
• The history of synaptic activity ('remembers')

  1. Allows synapse to become more efficient with higher rate of input (Long-term Potential, LTP), then return to normal rate of input

  2. Initially response is suppressed, but after some time responses go back to a level higher than the initial level <-- Tetanus (constant high)

  3. Also Long Term Depression (LTD)

  4. Occurs in part of brain for memory and learning
• • Spatial summation --> many different inputs get activated all at once, more inputs = greater response
  • Temporal summation --> repetitively active single input
  • Inhibitory inputs --> can be sent at the same time as the excitatory inputs to prevent neuron from responding
  • Neurons can integrate input - calculations of Inhibitory vs Excitatory, and AP threshold
• differences between skeletal muscle fibre AP and nerve cell AP

  A) 40 mv

  B) 1-2 mv

  C) -80 mv

  D) -70 mv

  E) -55 mv

  F) -55 mv

  
• Post-synaptic potentials (PSPs):

  • involves chemically gated channels (transmitter gated/ g-protein gated/ 2nd messenger gated)
  • graded response
  • long lasting (more than 1-2 msec)
  • no refractory period, can sum
  • amplitude adapts
  • conducted passively (electrotonically), decreases in size with distance
• Action Potentials (APs)

  • involves voltage-gated channels
  • all-or-none response
  • brief, 1-2 msec (except in muscles)
  • has refractory periods, cannot sum
  • amplitude does not adapt
  • is regenerated and propagated without loss of amplitude
• No. of transmitters released affects response (graded)

  No regeneration of PSP like in AP - current spreads fast but is leaky

  • Replenish the current using Action Potentials
  • Triggered along the axon hillock as there is a high density of Na+ voltage-gated channels & the threshold is at its lowest (-55 mV) here
  • Unfortunately, most synapses are at dendrites, not axon hillocks
  • Even at a hillock, a PSP does not have enough voltage to create an AP

   

  Solution: PSP Sums!