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)
- The major transmitters producing IPSPs are glycine and GABA (gamma amino-butyric acid)
- 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
- Image via Wikipedia
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