Neurotransmission

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Neurotransmission Neuromodulation

• B.Sc 2003

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Archetypal neurotransmitter is acetylcholine We
know more about cholinergic transmission than any
other. However, cholinergic transmission is the
exception not the rule in the CNS
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Acetylcholine can be very rapidly hydrolysed,
that is broken down by reaction with water. It
may be this characteristic that makes it suitable
as a transmitter
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Why is ACh a transmitter? What makes it
suitable? Ach is a quaternary amine it has a
nitrogen atom that is positively charged at one
end of the molecule Most compounds that are
agonists at cholinergic synapses also have a
positively charged nitrogen
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Some General Cholinergic agonists
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Two types of cholinergic agonists Nicotinic and
Muscarinic
Examples of Specific Nicotinic agonists
Nicotine, Lobeline
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Muscarinic agonists do not need positively
charged nitrogen
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Nicotinic ion channel openingMuscarinic
G-protein coupled

• M1 neural slow epsps in ganglia increase
  IP3,DAG
• M2 cardiac decrease heart rate decrease cAMP
• M3glandular increase secretion increase IP3

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Atropine scopolamine are antagonists at all
muscarinic synapses
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Transmitter release
Acetylcholine is found in synaptic vesicles (50
nm diameter), clustered around release zones in
the presynaptic membrane. Voltage-gated N- or P-
type calcium channels are found in large numbers
in the presynaptic membrane Blockade of these
channels (black widow spider venom, conotoxin)
prevents transmitter release
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After stimulation of axon, muscles normally show
an end plate potential that triggers AP. In
quiescent muscles, spontaneous miniature end
plate potentials are observed.
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Fact that mepps were quantized (2 mV, 4mV, 6 mV,
not e.g. 3.5 mV, was evidence that transmitter
was released in packets, or quanta. This led to
idea that transmitter was released from vesicles.
Even in absence of stimulation, some vesicles
were releasing transmitter
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Methods to study transmitter release mechanisms

• Toxins (mostly proteases) eg botulinus toxin,
  tetanus toxin
• Capacitance measurements of secreting cells
• Intracellular ion-sensitive dyes
• Mutation of intracellular vesicular membrane
  proteins

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Synaptic docking proteins On vesicle
synaptotagmin (sytg), synaptobrevin (syb) On
plasma membrane SNAP-25, syntaxin (sytx) In
cytoplasm NSF (contains ?-SNAP)
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Syb synaptobrevin, Sytg synaptotagmin,sytx
syntaxin
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Transmitter can leak from fusion complexes
before proper calcium triggering
Spontaneous release can occur from fluctuations
in intracellular calcium
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Studies on ACh receptors have used the electric
eeltorpedo as it contains very large amount of
receptor protein in the electroplax organ.
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Transmitter inactivation

• ACh uses enzymic breakdown as mechanism of
  inactivation
• All other transmitters use reuptake as
  inactivation mechanism

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• UNSOLVED PROBLEMS
• How does ACh unbind from binding site?
• What is actual mechanism of allosteric
  distortion?

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Cholinegic antagonists

• Depolarisation blockers eg suxamethonium
• Do not unbind from receptor, leave muscle
  depolarised and unable to fire second AP
• Curare-like agents bind to receptor but do not
  open ion channel

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