Neuroscience - Classical and peptide neurotransmitters Flashcards
What are the 5 criteria for an effective neurotransmitter?
1) Must be synthesised in the neuron from which it is released
2) Presynaptic stimulation leads to release
3) Application at postsynapse much have same effect as at presynapse
4) Agents that block the postsynaptic response should also block the exogenously applied putative transmitter
5) Response must be terminated rapidly
What is the lifecycle of a classical neurotransmitter
1) Accumulation of precursor in neuron
2) Precursor enzymatically metabolised to yield
mature transmitter
3) Uptake into vesicle by vesicular transport
4) Release by regulated exocytosis
5) Binding to postsynaptic receptor or presynaptic modulatory receptor
6) Re-uptake into nerve terminal or glia by plasma membrane transporter
7) Enzymatic degradation in synaptic cleft or nerve terminal
8) Diffusion from active site
When was acetylcholine first identified and classified as a neurotransmitter?
- Identified in 1913 by Henry Dale
- classified as a neurotransmitter in the 1920s be Otto Loewi and Dale
- Both won the nobel prize in 1936
How is acetylcholin synthesised? What is the enzyme?
- Choline acetyltransferase (ChAT)
> Transfers acetyl group from acetyl CoA to choline - Excess ChAT in nerve terminal
How is acetylcholine degraded?
- Breakage of ester bond of ACH
- Split into choline and acetate
- Choline is taken back up in pre-synaptic nerve terminal by choline transporter
What enzyme catalyses the breakdown of acetylcholine? Where is it found?
Acetylcholinesterase
- serine hydrolase
- inserted into post-synaptic membrane via short glycophospholipid or long collagen tails
What is a mutation in either enzyme associated with?
Associated with congenital myasthenic syndromes
What are the 4 biogenic amines? When were they discovered?
1) Noradrenaline - 1946
2) Dopamine - identified as neurotransmitter in 1950s
3) Serotonin - 1930s
4) Histamine identified as transmitter in 1970s
What are the catecholamines?
Dopamine and noradrenaline
Describe catecholamine synthesis from the phenylalanine precursor
Phenylalanine Tyrosine 3,4-dihydroxyphenylalanine (DOPA) Dopamine Noradrenaline Adrenaline
What enzyme catalyses each step?
1) Phenylalanine to Tyrosine
- phenylalanine hydroxylase (PAH)
2) Tyrosine to DOPA
- Tyrosine hydroxylase
3) DOPA to Dopamine
- DOPA decarboxylase
4) Dopamine to noradrenaline
- Dopamine-beta-hydroxylase
5) Noradrenline to adrenaline
- Phenylethanolamine N-methyltransferase
What type of enzymes are phenylalanine hydoxylase, tyrosine hydroxylase and dopamine-beta-hydroxylase?
Monooxygenases
- incorporate oxygen into an amino acid subtrate
What disorders are defects in PAH and TH associated with?
- Defects in PAH causes phenylketonuria (PKU)
- Defects in TH associated with dystonia and infantile parkinsonism
How does DOPA decarboxylase work?
Decarboxylates aromatic L-amine acids
What 2 enzymes are involved in Catecholamine degradation?
- Monoamine oxidase (MAO)
- Catecol-O-methyltransferase (COMT)
How do monoamine oxidases work?
- Oxidatively deaminates substrate to for inactive aldehyde derivatives
- These are further converted to glycol derivatives
What are the 2 forms of MAOs?
MAOA and MAOB
What do the 2 forms of MAO degrade?
MAOA higher affinity for noradrenaline and serotonin
Dopamine metabolised by both types
What do MAOs degrade dopamine to?
DOPAL
- this further degraded to DOPAC
What do MAOs degrade noradrenlaine to?
DOPEGAL
- further degraded to DOPEG
How do Catecol-O-methyltranferases work?
Transfrer a methyl group
What do COMTs degrade dopamine to?
3-Methyoxytyramine
What do COMTs degrade Noradrenaline to?
Normetanephrine
What occurs to the synthesis pathway in dopaminergic neurons?
Pathway terminates at DOPA decarboxylase and dopamine is packed into vesicles
Where are catecholamines degraded?
In the pre-synaptic nerve terminal
- requires reuptake
What are the 3 types of amino acid neurotrasmitters?
Glutamate
Gamma-aminobutyric acid (GABA
Glycine
How do amino acid neurotramsitters differ from catecholamines?
- Derived from glucose metabolism
- Taken up by glial cells as well as neurons
What are the 2 sources of glutamate in glutamate and gaba neurons?
1) Derived from the citric acid cycle
- alpha-ketoglutarate converted to glutamate by GABA-transaminase (GABA-T) in mitochondria
2) From glutamate reuptake
- Glutamate taken from cleft into glial cell
- Converted to glutamine by glutamine synthetase
- Glutamine transported to neuron
- Converted back to glutamate by glutaminase
- Can also be taken fro the cleft straight back into neurons
What happens to the glutamate in the pre-synaptic terminal?
Packaged into vesicles for regulated exocytosis
What occurs to the glutamate in GABAergic neurons?
Converted to GABA by glutamic acid decarboxylase (GAD)
What happens to the GABA after signalling?
Reuptake
- converted to succinic semialdehyde by GABA-T
- Succinic semialdehyde converted to succinate by succinic semialdehyde dehydrogenase which can rejoin the citric acid cycle
How do the 4 enzymes described work?
1) GABA-transaminase
- catalyses exhange of NH2 and =O groups between amino acid and keto acid
2) Glutamine synthetase
- aminates glutamate in an ATP dependent manner
3) Glutaminase
- deaminates glutamine to glutamate using water
4) Glutamic acid decarboxylase
- decarboxylates glutamate to GABA
Name some disorders that are a result of defective GABA/glutamate metabolism
- Epilepsy
- Cerebral palsy
- Obesessive-compulsive disorders
- Sleep disturbances
- Brain malformations and many more
How many (approx) peptide neurotransmitters are there?
At least 50 (more than classical transmitters!!!!)
Give some examples of peptide neurotransmitters and their functions
1) Substance P - pain perception
2) Opioids (endorphins etc) - analgesic effects
3) Neuropeptide Y - feeding behaviour, circadian rhythm, anti-depression effects
4) Oxytocin - social behaviours, fear and anxiety
- Somatostatin - locomotor and cognitive behaviour
What is the length of neuropeptide amino acid sequences?
Between 3 and 40 AAs
What is the life cycle of peptide transmitters?
1) Peptide synthesis in the cell body (transcription and translation)
2) Vesicle (large dense core) packaging and axon transport
3) Ca2+ dependent exocytosis
4) Receptor (G-protein coupled) binding
5) Inactivation:
- enzymatic (zinc-metalloproteases)
- Autoreceptor internalisation
- Diffusion
What is Dales Principle?
That a neuron is a single cell so all processes of the neuron may release the same neurotrasmitter
Interpreted to mean that a single neuron has 1 transmitter
What observation proves Dales Principle wrong?
A single neuron may have more than one neurotransmitter
For example, many neurons use classical and peptide transmitters (co-localisation)
What are the 3 advantages of co-localisation of neurotransmitters?
1) Different transmitter release to different stimuli
- e.g classical transmitters released at low frequency stimulation
- higher frequency stimulation leads to classic and peptide release
2) Modulation of signalling at single synapse
- co-released transmitters may modulate each other
3) Spatially restricting signalling
- different processes of presynaptic neuron may contain different neurotransmitters
