Download Neuroscience 4 – Neurotransmitters

Neuro 4a – Neurotransmitters
Anil Chopra
1. Define the essential steps in synaptic neurotransmission. Emphasise the
potential for therapeutic intervention in this process.
 Neurotransmission occurs at SYNAPSE
 Gaps are around 20nm between presynaptic and postsynaptic membranes.
 They can be
o Amino acids (glutamate, gamma amino butyric acid GABA)
o Amines (noradrenaline, dopamine)
o Neuropeptides (opioid peptides)
 These are stored in synaptic vesicles and then docked in the synaptic zone.
 Requires
o Ca2+ ions
o Ready vesicles in pre-synaptic membrane.
o Complex formation between vesicle, membrane and cytoplasmic
proteins. This allows quick vesicle docking and rapid responses to the
Ca2+ influx.
o ATP and vesicle recycling.
Process of Transmission
(1)
(2)
(3)
(4)
(5)
(6)
Action potential reaches membrane.
Causes opening of Ca2+ channels.
Transmitters in vesicles move toward and fuse with the membrane.
Neurotransmitter released into synapse. (Drugs are able to increase release.)
Neurotransmitter diffuses across gap.
Binds to receptor on post-synaptic neurone to bring about effect. (Drugs able
to block receptor & activate response)
(7) Transmitter inactivated (drugs
able to inhibit enzyme).
Activation of a CNS synapse
Synaptic
(8) Transmitter taken back into
vesicle
presynaptic cell and
Transmitter
repackaged.
Action potential
Synthesis of Transmitters
Transmitter
(1)
+
Transmitter
K+
a. Acetylcholine synthesised
++ K
from choline uptake into
Na+
ATP
nerve terminal.
Ca2+
b. Dopamine and
Transmitter
Na+
noradrenaline synthesised
Transmitter
from amino acid tyrosine.
c. GABA (gamma amino
Receptor
Na+
butyric acid)
d. Neuropeptides synthesised
in ribosomes
(2) Packaged into vesicles and docked in synaptic zone. Toxins target vesicular
proteins.
Excitatory Neurotransmitter receptor
Na+
excitatory postsynaptic potential
EPSP
V
2. Explain the differences between the
following and give examples.
-65 mV
Inhibitory Neurotransmitter receptor
5 msec
(i)
Cl-
Excitatory vs. Inhibitory Na+
Responses
V
inhibitory postsynaptic potenetial
IPSP
-65 mV
Excitatory - use glutamate (glutaminergenic)
- influx of Na+ ions
- Depolarise postsynaptic membrane
GLUTAMATE RECEPTORS
Inhibitory - use GABA (GABAergic)
- influx of Cl- ions
- Hyperpolarise postsynaptic
membrane
(ii)
Fast
Slow
Na +
Fast vs. Slow Synaptic
Potentials
- effect in μs to ms.
- Ion channel receptors
- Use Glutamate and GABA
- effect in seconds to minutes.
- G-protein coupled receptor
- Use dopamine and acetylcholine
(iii)
Na +
Ca2+
AMPA RECEPTORS
NMDA RECEPTORS
alpha amino-3-hydroxy-5-methyl4-isoxazole propionic acid
N-methyl-D aspartate
Majority of FAST excitatory synapses
Rapid onset, offset and
desensitisation
Slow component of excitatory
transmission
Serve as coincidence detectors
which underlie learning mechanisms
Ion Channel Receptor vs. G-Protein
Receptor
Ion channel receptor
Ion Channel - open up ion channels in postsynaptic
- Can be inhibitory or excitatory
- Use Glutamate and GABA in CNS
- Use Ach at neuromuscular junction
G-Protein - use cAMP as second messenger
- Use CNS and PNS with Ach, dopamine and
noradrenaline
FAST msecs
Mediate all fast excitatory
and inhibitory transmission
3. Give examples of clinical treatment which
acts by:
a. Increasing transmitter availability or
release.
L-DOPA is a precursor to dopamine so boosts production.
b. Reducing inactivation of transmitter.
Vigabatrin – inhibits GABA transaminase
c. Increasing activation of receptors.
Benzodiazepines – enhances the action of GABA
Phenobarbital – attaches to GABA receptors.
G-protein coupled
receptor
SLOW secs/mins
Second messenger e.g.
cyclic AMP cascade
greatly amplifies effect
d. Blocking receptor function
Those that block glutamate receptors.
4. Outline the roles of different neurotransmitter systems.
An inhibitory CNS synapse mediated
by gamma amino butyric acid GABA
glucose
TCAcycle
aKG
Glutamic acid
decarboxylase
GAD (B6)
GABA transporter GAT
GLUTAMATE
GABA transaminase
GABA-T
(1)
(2)
GABA
GABA
(4)
GABA
GABA
(3)
SSA
(7)
GABA
GABA
(6)
GLIAL
CELL
GABA
GABA receptor
(5)
GABAAR
Cl-
Cl-
Cl-
(1) Glutamate converted to Gamma amino butyric acid GABA by glutamic acid
decarboxylase.
(2) The GABA is packaged into vesicles.
(3) Released by exocytosis.
(4) GABA diffuses across the synapse.
(5) As it attaches to postsynaptic receptors, it causes and influx of Cl- ions.
(6) GABA is either taken back into the presynaptic neurone via GABA
transporters or into glial cells by excitatory amino acid transporter EAAT.
(7) In the glial cell, the GABA is converted to succinic semialdehyde by GABA
transaminase.
5. Explain functional deficit in epilepsy and how it can be treated with drugs that
influence excitation and inhibition.
Excess glutamate means over stimulations of postsynaptic neurone which leads to
continuous firing of action potentials and can result in a seizure (epilepsy). Anti
epileptic drugs can work by:
 Enhancing the GABA-mediated inhibition of conduction of nerve impulse
across a synapse e.g. Vigabatrin.
 Stopping the inactivation of GABA valporate.
 Inhibiting glutamate (glutamate antagonists) e.g. Phenobarbital.