Neurotransmitters Flashcards
(101 cards)
1
Q
Describe the synthesis of noradrenaline:
A
Tyrosine is converted into dopa by tyrosine hydroxylase (TH)
Dopa is converted into dopamine by dopa decarboxylase (DDC)
Dopamine is converted into noradrenaline by dopamine beta hydroxylase (DBH)
Note DBH is only found in noradrenaline neurons, not dopamine neurons.
2
Q
Describe the storage of noradrenaline:
A
70% stored in vesicles in nerve terminals (protected from breakdown), the rest is free in the cytoplasm.
3
Q
Describe the release of noradrenaline:
A
Calcium-dependent
4
Q
Describe the inactivation of noradrenaline:
A
- Re-uptake (specific transporter)
- Metabolism
Noradrenaline is broken down by catechol-O-methyl transferase (COMT) extracellularly or monoamine oxidase (MAO) in mitochondria of neurons and glia.
5
Q
Describe the pathways of noradrenaline:
A
a) Locus cereleus within the brainstem, axons project to the cerebellum, thalamus, hypothalamus, hippocampus, cerebral cortex, through the dorsal noradrenergic bundle.
b) Brainstem nuclei, descending pathways to the spinal cord.
6
Q
Describe the functions of noradrenaline:
A
Noradrenaline does not function like a classical neurotransmitter, produces a mixture of slowly developing and more sustained excitatory and inhibitory effects that involve changes in potassium conductance coupled with facilitation of responses to other neurotransmitters (sets the tone of neurons).
Locus cereleus involved in attention and learning.
Blood pressure regulation.
Thermoregulation.
Pain control in spinal cord.
7
Q
Describe the noradrenaline receptors:
A
alpha1A - increase in calcium
alpha1B - increase in IP3/DAG
alpha2A and alpha2B - decrease in cyclic AMP
beta1,2,3 - increase cyclic AMP
8
Q
Describe the synthesis of serotonin (5-HT):
A
L-tryptophan is converted into 5-hydroxytryptophan by tryptophan hydroxylase.
5-hydroxytryptophan is converted into 5-hydroxytryptamine (5-HT) by L-aromatic acid decarboxylase.
9
Q
Describe the storage of serotonin:
A
In vesicles.
10
Q
Describe the release of serotonin:
A
Fusion of vesicles to cell membrane calcium-dependent.
11
Q
Describe the inactivation of serotonin:
A
- Re-uptake - high affinity active transport (this is the molecular target for prozac).
- Metabolism - 5-HT is metabolised to 5-HIAA (5-hydroxyindoleacetic acid) by MAO.
12
Q
Describe the localisation of serotonin:
A
Cell bodies containing 5-HT are clustered in the midline region of the brainstem in an area called the raphe nuclei.
Ascending projections to the basal ganglia, hippocampus, cortex and cerebellum.
Descending projections to spinal cord.
13
Q
Describe the functions of serotonin:
A
Sleep, mood control (anti-depressants), appetite, anxiety and analgesia.
Serotonin is very important in depression and anxiety.
14
Q
Describe the serotonin receptors:
A
5-HT1A - decreases cyclic AMP 5-HT1B - decreases cyclic AMP 5-HT1C - increases IP3/DAG 5-HT1D - decreases cyclic AMP (5-HT1 receptors decrease neurotransmitter release and are pre-synaptic)
5-HT2 - increases IP3/DAG post-synaptic
5-HT3 - modulates neurotransmitter release (modulates dopamine systems pre-synaptically)
15
Q
Describe the synthesis of dopamine:
A
Tyrosine is converted in Dopa by tyrosine hydroxylase (TH)
Dopa is converted into dopamine by dopa decarboxylase (DDC)
16
Q
Describe the storage of dopamine:
A
75% in vesicles where it is protected from MAO, a degradative enzyme.
17
Q
Describe the release of dopamine:
A
Calcium-dependent vesicle fusion with membrane.
Most dopamine is released from axon terminals (classical neurotransmission), however, it can also be released from dendrites in the substantia nigra pars compacta.
18
Q
Describe the inactivation of dopamine:
A
- Re-uptake by the dopamine transporter, selective for dopamine, some taken back up into vesicles and reused, the rest metabolised.
- Metabolism.
19
Q
Describe the metabolism of dopamine:
A
Dopamine is converted into DOPAC by MAO(B), which is converted into homovanillic acid (HVA) by COMT.
Dopamine is converted into 3-methoxytyramine by COMT, which is converted into homovanillic acid by MAO(B).
20
Q
List the three main pathways of dopaminergic neurons:
A
- Nigro-striatal
- Mesolimbic/mesocortical system
- Hypothalamic
21
Q
Describe the nigro-striatal dopamine pathway:
A
Cell bodies are located in the midbrain substantia nigra parc compact (SNc), part of the extrapyramidal motor system. Their axons project to the striatum. This pathway is lost in Parkinson’s.
22
Q
Describe the mesolimbic/mesocortical dopamine system:
A
Cell bodies are located in the ventral tegmental of the midbrain, close to and some with SNc. Their axons project to the ventral (lower) striatum, limbic system and frontal cortex. This pathway is thought to be overactive in Schizophrenia.
23
Q
Describe the hypothalamic pathway in dopamine:
A
Involved in neuro-endocrine control.
24
Q
Describe the D1 and D5 dopamine receptors:
A
D1 produces cyclic AMP elevation (Gs-linked), post-synaptic in the striatum and substantia nigra. SCH23390 is a selective antagonist.
D5 is like D1 structurally.
25
Describe the D2, D3 and D4 dopamine receptors:
D2 produces cyclic AMP reduction (Gi-linked), reduces phosphatidylinositol. Pre-synaptic in the nigrostriatal and corticostriatal pathways, post-synaptic in the striatum and SNc. Sulphride is a selective antagonist.
D3 and D4 have very low levels in the striatum but very high levels in the limbic system, nucleus acccumbens and pre-frontal cortex. Like D2 structurally.
26
Describe the functions of dopamine:
1. Neuromodulatory actions produced by tonically released dopamine. Inhibitory and excitatory in the striatum, inhibitory effects in the amygdala, pre-frontal cortex and nucleus accumbans.
2. Motor control (dopamine agonists increase movement via D1 and D2 receptors acting in the striatum and SNc).
3. Mood/psychosis.
4. Vomiting, dopamine receptors in the chemo-receptor trigger zone in brainstem produce vomiting.
5. Brain reward, release of dopamine in the nucleus accumbans mediates brain reward and is involved in drug dependence.
27
Describe the relationship between dopamine and cocaine addiction:
Binds to the dopamine transporter, increases dopamine in the synaptic cleft in the nucleus accumbens, producing a cocaine high and reward, thus cocaine dependence.
Cocaine addiction is highlighted by extremely strong cravings for cocaine, producing cocaine-seeking behaviour.
D1 agonists enhance cocaine-seeking behaviour.
D2 agonists diminish craving, might be useful in preventing relapse.
28
Describe the synthesis of glutamate:
Glutamine is converted into glutamate by glutaminase.
29
Describe the storage of glutamate:
Glutamate and sparatate are formed in the cytoplasm and they are present in nerve termins.
30
Describe the release of glutamate:
Calcium-dependent.
31
Describe the re-uptake of glutamate:
(a) neurons
(b) glia (astrocytes)
There is a high-affinity sodium-dependent process specific for glutamate and aspartate and a low affinity uptake which carries other amino acids as well.
32
Describe the metabolism of glutamate:
```
In glia (astrocytes) glutamate is enzymatically degraded:
Glutamate is converted into glutamine by glutamine synthase.
Glutamine is then released from glia and taken up by neurons where it is turned back into glutamate.
```
33
Describe the pathways of glutamate:
1. Corticofugal (cortico-striatal, entorhinal cortex to hippocampus, visual cortex to lateral geniculate and superior colliculus).
2. Allocortical (hippocampus to lateral septum).
3. Primary afferents in dorsal horn of the spinal cord.
4. Cortico-cortico projections (commisural fibres).
34
Describe the functions of glutamate:
```
Glutamate produces neuronal depolarisation, the brains main excitatory neurotransmitter.
Cognition
Memory
Movement
Sensation
Emotion
```
35
Describe the action of AMPA receptors:
These are ligand-gated ion channels.
Glutamate binds which opens the ion channel, leading to sodium ion influx into the neuron and resulting in neuronal depolarisation.
36
Describe the receptor subunit theory of the AMPA receptor:
AMPA receptor composed of multiple sub-units, GluR1-4.
Receptor with the GluR2 sub-unit pass sodium but not calcium. Receptors without GluR2 but with GluR3 can carry calcium ions. Ischaemic brain injury causes a down-regulation of the GluR2 sub-unit, whihc might promote brain damage by increasing calcium fluxes.
37
Describe the agonists and antagonists of the AMPA glutamate receptor:
Agonists: AMPA, glutamate, kainate
Antagonist: NBQX
38
Describe the action of Kainate receptors:
Ligand-gated ion channel.
Glutamate binds, sodium ion influx, neuronal depolarisation.
Receptor composed of sub-units GluR5-7.
39
Describe the agonists and antagonists of the Kainate glutamate receptor:
Agonists: Kainate, glutamate
Antagonist: NBQX
40
Describe the group I metabotrophic receptors:
These are G-protein linked and contain mGlu1&5.
Activate phospholipase C and depolarise neurons.
Group I antagonists are neuroprotective in model systems.
Glutamate produces IP3 and DAG through phospholipase C. This causes increased calcium release from intracellular stores and increased protein kinase C.
41
Describe the group II metabotrophic receptors:
```
Includes mGluR2&3. They are Gi-linked and inhibit adenylate cyclase and cause presynaptic depression.
Agonists at these receptors are neuroprotective in model systems, probably by:
Inhibiting neurotransmitter (glutamate) release.
Activating the production of endogenous neuroprotective molecules (e.g. TGFB1) by astrocytes.
```
42
Describe the composition of the NMDA glutamate receptors:
NMDA receptors are dual voltage and ligand gated ion channels comprising multiple binding sites.
a. NMDA/glutamate binding site, increased calcium.
b. Strychnine-insensitive glycine binding site, increases the probablity of channel opening. It also acts as a co-agonist with glutamate.
c. Phencyclidine (PCP/angel dust) binding site, produces a decrease in channel action (non-competitive antagonist) by binding in the open channel (open channel blocker).
d. Zinc binding site, inhibits receptor function.
e. Polyamine site, enhance binding of open channel blockers.
43
Describe how NMDA activation occurs:
Magnesium ion normally occupy the channel and prevent calcium entry,
Depolarisation of the neuronal membrane results in efflux of magnesium and influx of calcium ions through channel.
To activate, glutamate and glycine as well as depolarisation, resulting in increased calcium and effects.
44
Describe the pathological roles for glutamate:
Epilepsy, stroke, head injury, neurodegenerative diseases, schizophrenia, drug dependence and glioma formation.
45
Describe the synthesis of GABA:
GABA is the main inhibitory neurotransmitter in the brain.
Glutamate is converted into GABA by glutamic acid decarboxylase (GAD) and pyridoxalphosphate (VitB6).
GAD is only found in the cytoplasm of nerve terminals containing GABA. This is the rate-limiting step in GABA synthesis.
46
Describe the storage of GABA:
In nerve terminals, vesicular and non-vesicular storage.
47
Describe the release of GABA:
Calcium-dependent.
48
Describe the inactivation of GABA via re-uptake:
1. Re-uptake (sodium dependent)
(a) into nerve terminals where GABA can be reused or metabolised
(b) into astrocytes (glia) where GABA is metabolised
49
Describe the inactivation of GABA via metabolism:
2-stages:
GABA is convertedinto succinic semialdehyde by GABA transaminase (GABA-T) present in the mitochondria.
Succinic semialdehyde is converted into succinate by succinic semialdehyde dehydrogenase.
50
Describe GABA pathways in the brain:
GABA is widely distributed in the brain.
Most GABA neurons are localised interneurons (local circuit neurons) with short axons, although some are long projection neurons (striatonigral and striatopallidal) pathways which are involved in movement control and lost in Huntington's disease.
51
Describe the two functions of GABA and their receptors:
GABA inhibits neuronal activity:
A- direct chloride-mediated hyperpolarisation of dendrites and soma
B- decreased neurotransmitter release via a K+ conductance, also post-synaptic
52
Describe the GABA A receptor structure:
Ligand-gated ion channel, pentameric binding sites, allows chloride influx.
1. GABA binding site (produces chloride channel opening, chloride influx and hyperpolarisation)
2. Allosteric modulatory sites:
(a) Benzodiazepine (BZ) binding site. BZs increase the affinity of GABA for its receptor, increases duration of channel opening, thus increasing inhibition
(b) Barbiturate binding site. Increases the duration of chloride channel opening in response to GABA, increasing in inhibition
53
Describe the GABA A agonist/antagonist:
Selective agonist: Muscimol
| Selective antagonist: Bicuclline
54
Describe the GABA A receptor functions:
Neuronal inhibition: GABA A antagonists (bicuclline) produce seizures and agonists (muscimol) produce anti-convulsant effects. These receptors are important in epilepsy and in anxiety.
55
Describe the effects of benzodiazepines and inverse agonists:
Benzodiazepines bind to BZR to increase GABA action (agonists).
Flumazenil binds to BZR to block BZ effects (competitive antagonist).
B-carbolines bind to BZR to decrease GABA action (inverse agonists).
56
Describe the GABA B receptor:
G-protein linked receptor family and it opens a potassium channel which causes hyperpolarisation and increased inhibition. Inhibits neurotransmitter release.
It is located mainly pre-synaptically, but is also post-synaptic. Beclofen is used to treat spastic conditions (hyperexcitability of spinal cord) and there are high levels of GABA B receptors in the spinal cord.
57
Describe the effect of glycine:
Glycine is the main inhibitory neurotransmitter in the spinal cord (strychnine = competitive antagonist). It causes a chloride influx which increases inhibition by hyperpolarising neurons.
58
Describe the GABA B agonist/antagonist:
Agonist: Baclofen
Antagonist: Phaclofen
59
Describe glycine synthesis:
Serine is converted into glycine by serine hydroxymethyltransferase.
60
Describe the release of glycine:
Calcium-dependent.
61
Describe the inactivation of glycine:
By re-uptake into neurons and glia.
62
Describe the pathways of glycine:
Distributed in spinal cord and brainstem. It is the inhibitory neurotransmitter of the Renshaw cells in the spine that inhibit motor neurons.
63
Describe the glycine receptors:
1. Strychnine-sensitive chloride channel in the spine, which mediates inhibition.
2. Strychnine-insensitive binding site on the NMDA receptor, acting as an excitatory co-agonist.
64
Describe the basics of neuropeptides (storage, isolation, size):
Small (2-40 amino acid) peptides stored within vesicles within neurons in terminals. They are released following activity and lead to powerful biological effects.
Many were initially isolated in the gut/enteric nervous system, and now also found in brain and spinal cord.
Because NPs are chains of amino acids they are larger molecules than the classical neurotranmitters (single amino acids or derivatives).
40 discovered so far.
65
Describe how neuropeptides differ from classical neurotransmitters:
NPs are very potent, present in small quantities, synthesis and inactivation is difference.
66
Describe how neuropeptides and neurotransmitters are similar:
NPs can act as NTs and also as co-transmitters (neuromodulators), such as adenosine.
Release is calcium-dependent in both cases.
67
Describe the pathway of classical neurotransmitters:
```
Synthesis of enzymes
Axonal transport of enzymes
Uptake of precursor
Synthesis of neuromodulator
Release of neurotransmitter
Reuptake of neurotransmitter (into nerve terminals, astrocytes)
```
68
Describe the pathway of neuropeptide neurotransmitters:
```
Synthesis of peptide precursor
Processing of precursor
Axonal transport of precursor
Release of peptides
Metabolism of peptides
```
69
Describe the synthesis of neuropeptides:
Takes place in cell body, directed by RNA (ribosomes)
DNA-gene is transcribed into mRNA
mRNA is translated into the pre-propetide
Pre-propeptide converted into the propeptide
Propeptide is converted into peptides
70
Describe the conversion of the pre-propeptide into the propeptide:
The pre-propeptide has no biological activity and contains amino acid sequence of peptide and amino acid sequences that act as signals for synthesis.
The pre-propeptide enters the ER and is transported to the Golgi where the pre-sequence is removed.
71
Describe the conversion of the propeptide into the peptides:
Propeptide is packaged into granules for transport to the nerve terminal via microtubules.
72
Describe the storage of neuropeptides:
In large vesicles.
73
Describe the release of neuropeptides:
By calcium-dependent exocytosis (fusion of vesicle with cell membrane).
74
Describe the inactivation of neuropeptides:
No reuptake, therefore enzymatic degradation is the route of inactivation by Metallo-Peptidase. Therefore, precursor proteins are required to maintain adequate NP levels.
75
Describe the pathways of neuropeptides:
NPs are found in many regions of the brain and spinal cord.
76
Describe the functions of neuropeptides:
1. Many NPs are colocalised in neurons with "classical" NTs and depolarisation produces release of classical NT and NP. NPs acting in this way are co-transmitters and it is thought that they modulate the effects of classical NT by altering release and/or post-synaptic effects.
2. NPs can also act as primary NTs e.g. substance P in spine.
3. Once released NPs usually act more slowly than classical NTs (sec-min) and can diffuse away to act at a distance on other neurons with NP receptors.
77
Describe the receptor binding of neuropeptides:
Like classical NTs, NPs work by binding to cell surface receptors.
78
Name the two types of neuropeptides:
1. Tachykinins
| 2. Opiod peptides
79
Describe the tachykinin class of neuropeptides and distribution:
Substance P.
Distributed:
1. Primary afferents (pain) to dorsal horn of spinal cord (capsaicin, releases substance P)
2. Striato-nigral projection (colocalised with GABA)
3. Hypothalamus
In the spine substance P relays pain information.
80
Describe the three classes of opiod neuropeptides:
1. Enkephalins (pentapeptides): Tyr-Gly-Gly-Phe-Leu/Met (leu/met enk). Precursor is proenkephalin A.
2. Endorphins (31 amino acids). Precursor is proopiomelanocertin (POMC).
3. Dynorphin A1-7 (17 amino acids). Precursor is prodynorphin=proenkephalin B (also makes leu-enk).
81
Describe the distribution of enkephanlins:
Basal ganglia (motor output)
Thalamus (pain sensation)
Dorsal horn of spinal cord (pain sensation)
Periacqueductal grey (pain sensation, brainstem)
(NB opiates = heroin, morphine)
82
Describe the distribution of B-endorphins:
Pituitary/hypothalamus - neuroendocrine control.
83
Describe the distribution of dynorphin:
Spine (pain/inflammation)
Hippocampus (learning)
Basal ganglia
84
Describe the release of opiods:
Calcium dependent.
85
Describe the functions of opiods:
Pain - analgesia
Motor control
Excitatory and inhibitory
Brain reward and drug addiction (nucleus accumbens)
86
Describe the mu opiod receptors:
B-end>dynA>met>leu
Decreased cAMP, increased K+
Involved in brain reward and drug abuse pain control (morphine works here to control pain); respiratory depression subtypes.
87
Describe the delta opiod receptors:
leu=B-end=met>dynA
| Decreased cAMP
88
Describe the kappa opiod receptors:
DynA>>B-end>>leu-met ?
89
Describe a competitive antagonist for all three opiod receptors:
Naloxone.
| Antagonises morphine and heorin effects in the brain.
90
Describe the synthesis of acetylcholine:
Acetate and coenzyme A are converted into Acetyl-CoA and choline, which is converted into acetylcholine (Ach) by choline acetyltransferase (ChAT).
91
Describe the storage of acetylcholine:
In vesicles.
92
Describe the release of acetylcholine:
Calcium-dependent.
93
Describe the inactivation of acetylcholine:
Ach is degraded into acetate and choline by acetylcholinesterase (AchE).
94
Describe the muscarinic Ach receptors:
M1/3/5 Gq-linked, increase IP3 and DAG.
M2/4 Gi/o-linked, inhibit adenylate cyclase and decrease cAMP and increase potassium.
Agonist: Muscarine
Antagonist: Atropine
95
Describe the nicotonic Ach receptors:
The neuronal type is different from the muscle type.
Ligand-gated ion channel carries Na+, K+ and Ca2+.
Agonist: Nicotine
Antagonist: Bungarotoxin
96
Describe the 4 pathways of acetylcholine:
1. Ventral horn of spinal cord (neurons send their axons to skeletal muscle and are responsible for voluntary control of movement). Lost in Motorneuron disease.
2. Basal nucleus of Meynert (cholinergic neurons in the basal forebrain that project to the neocrotex and thalamus). Lost in Alzheimer's.
3. Medial septum (axons project to the hippocampus). Lost in Alzheimer's.
4. Ach interneurons = local circuit neurons (found in the striatum, cortex and brainstem).
97
Describe the functions of acetylcholine:
ACh is one of the two main excitatory neurotransmitters in the brain, it therefore has many functions including:
Learning and memory (M1 receptor, major target for the development of Cognitive Enhancers to treat Alzheimer's)
Movement control in the striatum (muscarinic antagonists are used to treat PD)
Muscarinic antagonists are anti-emetic (e.g. scopolamine)
Muscle control in spinal cord
98
Describe the muscarinic receptor mediation of learning and memory theory:
Suggests memories are stored in ensembles of neurons, with modified synaptic transmission.
Agents that modify the strength of synapses may be involved in memory formation.
99
Describe the production of Theta rhythm in memory formation:
The hippocampus has been implicated in forming new memories, displaying an EEG Theta rhythm (3-8Hz) when memories form.
Theta is partly produced by Medial Septal activation of M1 receptors in the hippocampus. This muscarinic receptor-mediated theta may prime the hippocampal synapses to make them more easily modified thereby producing new learning.
100
Describe the relationship between ACh and NGF:
ACh neurons in the medial septum contain low and high-affinity (p75 and TrkA) receptors for the neuronal survival/growth factor (neurotrophin) Nerve Growth Factor (NGF).
NGF maintains the cholinergic phenotype of medial septal neurons and is involved in their development. It is secreted by hippocampal neurons, is bound to p75 and transported down the axons to the cell body of the medial septum.
101
Describe the relationship between ACh, TrkA and Alzheimer's:
TrkA is a receptor tyrosine kinase that mediates the effectors of NGF on medial septal neurons.
Because ACh is lost in Alzheimer's disease and is the best predictor of the cognitive decline in this disease), recent clinical trials have attempted infusing NGF into human Alzheimer's disease brain.
A better strategy would be to develop drugs which act on the TrkA receptor and which can cross the blood/brain/barrier.
