SYNAPSES AND NEUROMUSCULAR JUNCTIONS OF NEURONS-TUTORIAL

Chemical Transmitters Carry the Signal Across Synapses & Neuromuscular Junctions

  • A contact between 2 nerves is called a synapse
  • At the synapse there is a break in electrical transmission (the action potential cannot cross)- instead chemicals are released that carry the signal to the next nerve
    • The release of chemical transmitters at nerve endings was first shown by Otto Loewi in the frog heart
  • A neuromuscular junction (NMJ) is a contact between a nerve and a muscle- it is like a synapse, the action potential stops and the signal is carried by a chemical
  • There is a delay at synapses- chemical transmission is slower than electrical transmission

Chemical Transmitters Are Made and Stored in the Presynaptic Terminal

  • The end of the nerve enlarges into an axon terminal
  • Transmitters are made in the terminal and are stored in tiny vesicles so that they can be released whenever an action potential comes along
  • Transmitters are made only by the incoming (presynaptic) nerve
  • Because the transmitter is only on one side the impulse can go in only one direction

Calcium is Required for Transmitter Release

  • Transmitter release requires Ca2+ ions
  • Normally Ca2+ in the cell is kept very low (by a Ca pump)- if the cell needs Ca2+ it must come from the outside
  • The action potential coming in to the terminal opens Ca channels -> Ca comes rushing in
  • The Ca2+ causes some of the vesicles to fuse to the membrane- then they open up and the transmitter is released
  • Botulinum and tetanus toxins block transmitter release

Transmitter Diffuses Across the Synaptic Gap and Binds to a Receptor

  • The synaptic gap is short and the transmitter travels across it by simple diffusion
  • On the far side of the gap the transmitter binds to a specific receptor protein in the postsynaptic membrane
  • There are some receptor diseases- in myasthenia gravis an autoimmune reaction destroys acetycholine receptors in the neuromuscular junction- this causes muscular weakness or paralysis
  • Many drugs block receptors: curare, strychnine, atropine, antihistamines

When Transmitter Binds to a Receptor it Produces an EPSP or an IPSP

  • When the transmitter binds to the receptor ion channels are opened (ligand-gated channels)
  • Ions rush into the postsynaptic cell
  • If the ions depolarize the postsynaptic cell they produce an excitatory postsynaptic potential (EPSP)
    • Most transmitters produce EPSPs (acetylcholine, epinephrine, norepinephrine)
  • If the ions make the postsynaptic membrane more negative they produce an inhibitory postsynaptic potential (IPSP)
  • There are both excitatory and inhibitory nerves coming into most synapses

If There Are Enough EPSPs an Action Potential Will be Produced in the Postsynaptic Membrane

  • If there are enough EPSPs the postsynaptic membrane will be depolarized to the threshold level and an action potential will be produced- then the signal will travel along the second nerve or muscle cell
  • IPSPs make the membrane potential more negative and cancel out EPSPs

The Transmitter is Broken Down and/or Recycled

  • Once the signal has been delivered the transmitter must be removed so that new signals may be received
  • In some cases the transmitter is broken down by an enzyme in the synapse
  • In other cases the transmitter is recycled- it is transported back into the presynaptic nerve
  • In still other cases these 2 methods are combined
  • Some drugs inhibit the enzymes that break down transmitters: nerve gases, physostigmine
  • Other drugs act by inhibiting recycling: prozac, cocaine

In the Central Nervous System Nerves Make Synapses with Thousands of Other Nerves

  • Nerves in the central nervous system make synaptic contact with 1000 to 10,000 other nerves
  • This allows nerve cells to be hooked together in complex patterns to perform tasks benefiting the animal
  • In the brain synapses tend to cluster to form ganglia (gray matter of brain)
  • Each nerve makes both excitatory and inhibitory synapses
  • Whether or not a nerve fires is determined by summation of the EPSPs and IPSPs

There are Dozens of Transmitters in the Nervous System

  • In this class we will deal with only a few types of transmitters: acetylcholine, epinephrine, norepinephrine and a few others
  • There are dozens of other transmitters in the central nervous system (CNS) and new ones are being discovered every year:
    • Serotonin, dopamine, glutamate, secretin, endorphins, etc.
    • Even gas molecules such as nitric oxide (NO) can act as local transmitters
      • The gas types are not stored, but are made on demand
  • A high percentage of pharmaceutical drugs affect the synapse or NMJs

Synapses Are Believed to be the Sites of Learning and Memory

  • Many learning exercises are known to increase transmission across certain synapses (potentiation). The potentiation can be for short or long term
  • Long term potentiation involves protein synthesis, probably of receptors

Many Toxins and Diseases Affect Neuromuscular Junction & Synaptic Transmission

  • NMJs and synapses are attacked by toxins and poisons:
    • ACh release in the NMJ is inhibited by botulinum toxin
    • Glycine release in the central nervous system (CNS) is inhibited by tetanus toxin
    • Black widow spider toxin, alpha-latrotoxin, stimulates fusion and depletion of transmitter vesicles
    • The plant poison, physostigmine, nerve gases and organophosphorus pesticides inhibit acetylcholinesterase, the enzyme that splits ACh into acetate and choline
    • The muscle ACh receptor is blocked by the South American arrow poison, curare
    • The plant drug, atropine, inhibits ACh receptors of the autonomic nervous system (but not the NMJ)
    • Strychnine binds to the glycine receptor protein and inhibits IPSPs in the spinal cord
    • Cocaine blocks the recycling of of dopamine and norepinephrine transmitters in the brain. This has an excitatory effect
    • Acetylcholine in synapses and NMJs is affected by 3 different types of inhibitors: release inhibitors, receptor inhibitors and acetylcholinesterase inhibitors.
  • Low blood Ca will inhibit transmitter release
  • Diseases affecting synapses and NMJs:
    • Eaton-Lambert syndrome: patient produces antibodies that attack his own Ca channels. This results in low Ca in the synapse and transmitter release is inhibited
    • Myasthenia gravis: another autoimmune disease which damages the receptor proteins for ACh
    • Parkinson’s disease: cells in the substantia nigra of the brain are deficient in the transmitter, dopamine
    • Clinical depression: associated with low amounts of the transmitter, serotonin, in parts of the brain

A Detailed Example: the Neuromuscular Junction

  • We will consider the NMJ in detail because it is the best known junction. The diagram below outlines reactions in the NMJ.
  • Transmission at this junction involves several steps:
    • 1) When an action potential (inhibited by tetrodotoxin) reaches the axon terminal it causes Ca channels to open. Ca2+ rushes into the cell because Ca2+ outside is much higher than Ca2+  inside
    • 2) The terminal region is loaded with vesicles containing the transmitter acetylcholine (ACh)
    • 3) Ca2+ causes some of the vesicles to fuse with the membrane and release their ACh (inhibited by botulinum toxin)
    • 4) ACh diffuses across the junction and binds to the ACh receptor protein (inhibited by curare) in the postsynaptic membrane
    • 5) Binding causes an ion channel to open
    • 6) The flow of ions depolarizes the membrane, producing an EPSP. In muscle a single impulse usually causes enough depolarization to reach threshold
    • 7) An action potential is generated in the muscle membrane
    • 8) The muscle action potential causes release of Ca2+ from the sarcoplasmic reticulum of the muscle and this triggers muscle contraction
    • 9) Back in the synapse the ACh is broken down to acetate and choline by the enzyme acetylcholinesterase (inhibited by physostigmine, nerve gases, organophosphate insecticides).
    • 10) The choline is recycled. A choline pump transports it back into the nerve terminal and there it is converted back into ACh
      Detailed view of a neuromuscular junction:<BR>...
      Image via Wikipedia
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