Week 3 Topic 2 - Neurotransmitters, receptors and pathways Flashcards
neurotransmitter systems
Hello, my name’s Jon Robbins. I’m a neuroscientist at King’s College London. This Subtopic 2 is going to be on
neurotransmitter systems. And you will have learned already that the neurons interact with each other by
releasing neurotransmitters. You will have already heard about the synapse, in Subtopic 1, where this occurs.
I have simplified this system into something I call the 2S, 3R, 2D system. The first ‘S’ stands for ‘synthesis’, the
second – ‘storage’. The first ‘R’ is ‘release’, the second – ‘receptors’, the third – ‘re-uptake’. For ‘D’ – ‘D’ stands
for ‘degradation’ and the final ‘D’ stands for ‘drugs’ that are targeted on the system and ‘diseases’ that involve
it.
Slide 5:
The synapse, as you already know, is made up of two sections – the presynaptic terminal and the postsynaptic
region. In between is the synaptic cleft. Synthesis occurs in the presynaptic terminal, along with storage, and reuptake, and degradation. The neurotransmitter is released into the synaptic cleft and can work on a number of
receptors which can be found both postsynaptically and presynaptically.
Slide 6:
GABA
It’s called ‘gamma aminobutyric
acid’. That’s rather a mouthful, so we’ll usually call it ‘GABA’. Again, it’s an amino acid. It’s widely distributed in
the central nervous system and it’s at about 30 per cent of the synapses in the brain. There’s very little in the
peripheral nervous system and this is probably the most important inhibitory neurotransmitter in the central
nervous system.
TYPE: an amino acid. It’s widely distributed in
the central nervous system and it’s at about 30 per cent of the synapses in the brain. There’s very little in the peripheral nervous system and this is probably the most important inhibitory neurotransmitter in the central nervous system.
SYNTHESIS
GABA is synthesised from glutamate – which is the first ‘S’ – by an enzyme called ‘glutamic acid decarboxylase’.
So, its synthesis is relatively straightforward.
STORAGE
It is stored, like glutamate, in vesicles, but the transporter that moves it into these vesicles is called ‘vesicular
GABA transporter’, or ‘vGABAT’. Again, the vesicles also have a proton pump that fill them up with hydrogen
ions which they use to exchange for the GABA neurotransmitter. And this is a common occurrence for vesicles.
So, that’s the second ‘S’ – storage.
RELEASE
The first ‘R’ is release. And, again, this will be a common occurrence. Again, it’s a calcium dependent vesicular
release for GABA and this mainly occurs at the axon end terminal bouton.
RECEPTORS
Receptors, once again, can be subdivided into two major classes. The ionotropic receptors, which are called
the ‘GABA-A’ receptor, which is actually, in this case, an ion channel for chloride ions rather than the sodium
and calcium. So, it allows negative ions into the cells. The metabotropic glutamate receptors associated with
GABA are the ‘GABA-B’ receptors and they are coupled to the G-proteins, ‘Gi’ and ‘Go’.
REUPTAKE
Like glutamate, GABA is released into the synaptic cleft. Once it’s done its job of binding to the receptors, it can
then be transported back, once again, into neurons and into glial cells – particularly astrocytes. The transporter
protein that moves it into neurons is called the ‘GAT1’ or the ‘Neuronal GABA Transporter’. And the one that
transports it into glia is appropriately named the ‘Glial GABA transporter’, ‘GAT3’.
DEGRADATION
Degradation occurs by an important enzyme called ‘GABA transaminase’. And this occurs mostly in glial cells,
such as astrocytes. a-Oxoglutarate is converted to glutamate and, at the same time, GABA is converted to an
inactive compound called ‘succinic semialdehyde’.
DRUGS
Finally, we talk about subset ‘D’, the last one, which includes drugs. And, here, I’ve shown drugs under the terms
of receptors. And some famous drugs – that are used not clinically, necessarily – that act on the GABA A
receptor are ‘muscimol’, which is an agonist and activates the receptor, ‘bicuculine’, which is a competitive
antagonist, and ‘picrotoxin’, which is a GABA receptor channel blocker. Some of the clinically useful drugs that
act on the GABA A receptor are the benzodiazepines, ethanol and many general anaesthetics – as these are all
positive allosteric modulators of the GABA A receptor.
For the GABA B receptor, ‘baclofen’ is an agonist and ‘saclofen’ is a competitive antagonist. Good examples of
drugs that interfere with GABA re-uptake is ‘tiagabine’, which blocks GAT or the GABA transporter. And
another drug, which is ‘vigabatrin’, blocks the important enzyme, GABA transaminase. So, there’s a number of
places where you can interfere with the GABA synaptic transmission.
DISEASE
The last ‘D’, here, is disease. I’ve indicated some recreational drugs – of which barbiturates are a good example
– that act on GABA A receptors. The diseases you might be expected to find associated with GABA are
epilepsy, anxiety, and insomnia. GABA has a major function in the central nervous system particularly
associated with inhibitory actions of the brain.
GABA FACT SHEET
I’ll now move onto my fact sheet for GABA. Again, it’s in the same style as I’ve shown you before. Down the left
are the six letters and what I’ve identified is the important aspect for each of these for GABA.
So, the synthetic enzyme is ‘GAD’, the storage is ‘vesicular’, the release is ‘calcium dependent at the terminal’,
and the receptors can be subdivided into ‘ionotropic GABA A receptors’ and ‘metabotropic GABA B receptors’.
Reuptake is by GABA transporter and degradation is by the enzyme ‘GABA transaminase’.
On the right, clinically used drugs indicated in green are ‘muscimol’ and ‘bicuculline’ – for the GABA A receptor –
and the clinically used drugs that act here are benzodiazepines and anaesthetics. For the GABA B receptor,
‘baclofen’ is used clinically and ‘saclofen’ is a synthetic compound that is used for investigation action of
receptors. As I previously mentioned, ‘tiagabine’ blocks the GABA transporter and ‘vigabatrine’ blocks the
enzyme that breaks down GABA. So, these drugs are used clinically.
Now we come on to my third example neurotransmitter – ‘dopamine’. This is a monoamine
Now we come on to my third example neurotransmitter – ‘dopamine’.
TYPE: This is a monoamine. And you can see it’s
located in specific areas in the central nervous system. It has a more restricted distribution.
PATHWAYS and DISEASES: For example,
important pathways – the nigrostriatal pathway is dopaminergic and this one is particularly associated with PARKINSON’S disease; the mesocortical pathway is also dopaminergic and that is associated with SCHIZOPHRENIA.
So, you can see the distribution of cells that release dopamine are much more restricted than you see for
glutamate and for GABA.
SYNTHESIS
My first S for this neurotransmitter is synthesis again. And this is a three step process where tyrosine is taken
in by the diet and the rate limiting enzyme that converts this to DOPA is tyrosine hydroxylase. DOPA is
converted to dopamine by dopamine decarboxylase.
Slide 6:
STORAGE
Storage, as before, occurs in vesicles. And these vesicles are very acidic, as before, because they also have
the proton pump. And there are two types of vesicular monoamine transporters, called ‘VMAT1’ and ‘VMAT2’.
And these can be cell type specific. Some dopaminergic neurons have one and, some, two. So, you can see this
is a consistent event occurring commonly with many neurotransmitters.
RELEASE
Dopamine is released. And, here, there’s some variation. It is calcium dependent, as normal. It occurs at the
end terminal, as normal. But you also get a release that’s called ‘en passant’. And that’s where you have small
release sites that occur all the way down the axon, as shown on this slide. And these varicosities can release
dopamine all the way down, as the axon travels through tissue, as well as dopamine being released at the
terminal end, as normal.
TYPE OF RECEPTORS:
Dopamine receptors all of one type. They’re all G-protein coupled – or ‘metabotropic’ – class type. There are
no ligand-gated ion channels for dopamine. They can be, again, subdivided into ‘D1-like’ and ‘D2-like’. The ‘D1-like’
family are ‘D1’ and ‘D5’. And they’re coupled to their G-protein, ‘Gs’. Whereas the ‘D2-like’ family, include ‘D2’,
‘D3’, and ‘D4’. And they’re coupled to G-proteins – ‘Gi’ and ‘Go’.
REUPTAKE
Like before, once released, dopamine can be re-uptaken back into the neuron. And that’s by something called
‘DAT’ – ‘dopamine active transporter’. And that’s co-transported with one chloride ion and two sodium ions.
DEGRADATION
The degradative pathway, the first D, is complicated. Dopamine can be degradated through a lot of steps to
reach the common, final product, which is usually homovanillic acid.
As you can see from this slide, you can go straight down– where dopamine is first converted by monoamine
oxidase– and then an intermediate is converted into dihydroxyphenylacetic acid by catechol-Omethyltransferase.
Conversely, dopamine can be converted by catechol-O-methyltransferase into three 3-methoxydopamine and
then, by MAO, down to homovanillic acid. So there are a number of biochemical pathways that can lead to the
breakdown of dopamine.
DRUGS AND DISEASE
For our drugs and disease section, an important drug, ‘levodopa’, used to treat Parkinson’s disease is a
precursor for dopamine and, therefore, increases the amount of dopamine in peoples’ brains who have lost a
component of it. A number of important drugs work on the storage of dopamine. And these work by blocking
the vesicular transporter. And these drugs are ‘reserpine’ and ‘methamphetamine’.
Drugs that interfere with release – ‘amantadine’ is a good example. And then some of the drugs that work on
the receptors – full agonists – include dopamine itself, a compound called ‘apomorphine’ and ‘bromocriptine’.
Competitive antagonists which are clinically used – ‘haloperidol’ and ‘chlorpromazine’ are also available.
Reuptake of dopamine – a number of drugs work here – cocaine, for one, ‘bupropion’ and ‘methylphenidate’ –
which is also called ‘Ritalin’ – work at this point.
And then there are a number of important drugs that interfere with the degradation of dopamine – the
monoamine oxidase inhibitors, ‘phenelzine’ and ‘selegiline’, and the COMT inhibitors, ‘entacapone’ and
‘tolcapone’.
Slide 12:
Then we can talk a bit about the recreational drugs that interfere with the dopaminergic system and there are
some very famous, or infamous, ones here – cocaine, amphetamines and a rather unusual compound called
‘bromocriptine’, which can be found in the fungal contamination of grain and adds an important historical
contribution to some of the psychosis that occurred when abnormal fungal were growing on the wheat used to
make bread in the Middle Ages.
The famous disease association with dopamine is Parkinson’s disease, but also schizophrenia – as you’ll find out
later in the modules – also hormonal disturbances and drug dependence all involve the dopamine
neurotransmitter system. What’s its role in the brain? Well, it’s possibly involved with reward systems, it’s
Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content.
Week 3 @ King’s College London 2019 3.
certainly involved in motor control and it possibly has an important role in thought processes and definitely in
pituitary control of hormones.
Slide 13:
The fact sheet, as before – we’ve got our six letters down the left-hand side.
SYNTHESIS - And, for dopamine, the synthetic
enzyme is ‘tyrosine hydroxylase’.
STORAGE - The storage is by ‘vesicular process’.
Again, we’ve got ‘calcium dependent terminal’ and, this time,
RELEASE ‘en passant’ release.
RECEPTORS Dopamine receptors, all Gprotein coupled receptors of five subtypes.
REUPTAKE The re-uptake protein is called ‘DAT’. And there are a number of
enzymes involved in its
DEGRADATION
degradation – ‘monoamine oxidase’ and ‘catechol-O-methyltransferase’.
Many more drugs of clinical use are identified here – ‘L-DOPA’, which affects syntheses, ‘amantadine’, which can
cause neurotransmitter release.
DRUGS AND DISEASE
And then a number of drugs, such as ‘apomorphine’, ‘haloperidol’ and
‘chlorpromazine’ – some of which are used for schizophrenia treatment. I’ve already indicated that
‘methylphenidate’ is used for some mental problems. And then there are some compounds that are used as
adjuncts with L-DOPA and can be used to help treat Parkinson’s disease.
My last neurotransmitter today is ‘5-HT’ or ‘5-Hydroxytryptamine’. It’s also called ‘serotonin’ and it’s another
monoamine or, indeed, it’s, more specifically, an indolamine. Like dopamine, it has a very restricted distribution.
SEROTONIN
My last neurotransmitter today is ‘5-HT’ or ‘5-Hydroxytryptamine’. It’s also called ‘serotonin’ and it’s another
monoamine or, indeed, it’s, more specifically, an indolamine. Like dopamine, it has a very restricted distribution.
As you can see, there’s one major nucleus that contains the cell bodies of these neurons, which is the ‘raphe’.
And these project almost to everywhere in the brain. So, the cell bodies are all located in one part of the brain,
but the projections go all over the brain. It’s also found in quite high concentrations in the enteric nervous
system, but we won’t be discussing that now.
SYNTHESIS
As with dopamine, there are three steps to its synthesis. You’ve got ‘tryptophan’ taken into the diet.
‘Tryptophan hydroxylase’ is the rate limiting enzyme which converts it to 5-Hydroxytryptophan. ‘DOPA
decarboxylase’ then finally converts it to the 5-HT, which is the active neurotransmitter.
STORAGE
The second ‘S’ – storage. Again, a very similar picture to the one we saw before. We’ve got the same
transporters – ‘VMAT1’ and ‘VMAT2’ – which transport 5-HT into the vesicles, again requiring hydrogen ions to
be pumped out in exchange.
RELEASE
The release is calcium dependent, mainly on the axon terminal bouton but, interestingly, it can be co-released
with other neuropeptides, such as ‘somatostatin’ or ‘substance P’.
RECEPTORS
Receptors fall into the two classifications, as before. You have the ligand-gated ionotropic receptor, which is
the ‘5-HT3’ receptor, and that’s the only example of a 5-HT receptor that is a ligand-gated ion channel. This is a
mixed cation channel, so it allows sodium and calcium into the cell and a little bit of potassium out.
The big list of G-protein coupled receptors, which are shown here, indicate a list of at least six families – ‘1’, ‘2’,
‘4’, ‘5’, ‘6’ and ‘7’. And these are subdivided by what G-proteins that they couple to, as we saw before. So, for
example, the ‘5-HT1’ receptor family are mainly coupled to the G-proteins ‘Gi’ and ‘Go’ and, more than likely,
found on the presynaptic nerve terminal. Whereas, the ‘5-HT2’ family couples to a different set of G-proteins –
‘Gq’ and ‘G11’ – which are usually postsynaptic. I will point out that the ‘5-HT5B’ receptor, although found active
in animals, is a pseudogene in humans – so it does not actually get expressed.
REUPTAKE
Reuptake – again, as before, diffusion of the 5-HT away from the synaptic cleft leads to its re-uptake by a
particular protein called the ‘serotonin transporter’ or ‘SERT’, for short. Again, chloride and two sodium ions
are co-transported with it to get it back into the presynaptic terminal.
DEGRADATION
Degradation – the first ‘D’. 5-HT is converted by monoamine oxidase into ‘5-hydroxyindolealdehyde’. And then
the second enzyme, ‘aldehyde hydrogenase’, converts it into ‘5-HIAA’, which is the common metabolite that
monitors 5-HT.
Slide 11:
Then we come to drugs and disease. Important drugs – ‘L-tryptophan’ is an important precursor for the
synthesis of 5-HT. It’s often used as a drug in depression. An example of a drug that works on the receptors for
5-HT is ‘sumatriptan’, which is used for migraine treatment. There are also competitive antagonists, such as
‘ondansetron’ and ‘ketanserin’. Reuptake of 5-HT can be blocked very specifically by ‘citalopram’, which is a
serotonin selective re-uptake inhibitor used for depression, as is ‘imipramine’ and the monoamine oxidase
inhibitor, ‘phenelzine’. You’ll hear more about these drugs as the module and course goes on.
DRUGS
5-HT has quite a large list of recreational drugs: amphetamines and its derivatives – particularly MDMA (or
ecstasy, as it’s commonly known); LSD, a very famous one, works on this system and so does ‘mescaline’ and
‘psilocybin’. And psilocybin comes from magic mushrooms.
DISEASES
Important diseases associated with 5-HT are
depression, anxiety and hallucinations. As you can see, a number of the recreational drugs can produce those
effects. So, therefore, 5-HT is probably important in mood, the sleep/wake cycle and appetite.
Slide 13:
FACTSHEET
Now we go to the fact sheet for 5-HT or serotonin. Again, down the left-hand side, as before, are the six letters.
And I fill in, here, the particular important bits, which include ‘tryptophan hydroxylase’ as the synthetic enzyme,
‘vesicular’ storage, ‘calcium dependent’ release at the ‘terminal’. And then we have examples of the receptors
that it works on, the re-uptake system ‘serotonin transporter’, and the important enzymes involved in its
degradation – ‘monoamine oxidase’ and ‘COMT’.
On the right-hand side, we see a list of drugs which ‘L-tryptophan’ is used clinically, so is ‘ondansetron’ and
‘sumatriptan’. And, again, we can identify which drugs are clinically used by colouring them green, whereas the
others are useful compounds for studying the 5-HT system and maybe not used in humans.
Slide 16:
So, I’ve just given you four important neurotransmitters in the brain, but they’re only four of the 30 you may
come across. I’ve given you a list, here, of others that are important and you are likely to come across in this
course, including ‘acetylcholine’, ‘ATP’ – ‘adenosine triphosphate’ – ‘bradykinin’, ‘glycine’, ‘histamine’, a whole
range of neuropeptides – a couple of which I’ve already mentioned – ‘nitric oxide’ and ‘noradrenaline’.
What I would suggest, as you go through the course, is make your own fact sheets as you find out about these
neurotransmitters. And this will really help you build up your knowledge and get you a good understanding of the
important roles of these molecules in the central nervous system.
Glutamate
The first neurotransmitter I’m going to talk about is a very important one – it’s called ‘glutamate’ or ‘glutamic
acid’. It’s an amino acid widely distributed in the central nervous system and it occurs at about 70 per cent of all
synapses. There’s very little glutamate in the peripheral nervous system. Indeed, glutamate is the most
important excitatory neurotransmitter in the central nervous system.
SYNTHESIS
The first ‘S’ in my system is ‘synthesis’. So, this is how the neurotransmitter is manufactured, as required in the
neuron. In fact, for glutamate, the synthesis occurs in two sorts of cells – on the left, in glial cells, and on the
right, in a neuron. In glial cells, oxoglutarate is converted into glutamate by GABA transaminase. And on the
right, in neurons, glutamine is turned into glutamate by glutaminase.
STORAGE
The manufactured glutamate is stored in organelles called vesicles. The method by which glutamate gets into
these vesicles is by a special protein, called a ‘transporter’. And this is particularly called a vesicular glutamate
transporter. There are at least three types of vesicular glutamate transporter known and they all have this
function of pumping glutamate into the vesicle. To get the glutamate in, hydrogen ions are pumped out. And this
allows a concentration of glutamate in the vesicle to reach quite high concentrations – up to 20 millimolar. The
high level of hydrogen ions found in vesicles that make them acidic and is used to pump in the glutamate is
produced by a proton pump, which converts the energy of ATP into the higher concentration of hydrogen ions in
the vesicle, which can then be exchanged for neurotransmitter. So, that is our storage part.
RELEASE
Neurotransmitters, as you already know, are released by the nerve terminal at the axon terminal bouton. And
these are released in a calcium dependent process. Calcium is required to both move and fuse the vesicles with
the membrane to allow the neurotransmitter into the synaptic cleft.
RECEPTORS
Once in the synaptic cleft, the neurotransmitter – in this case, glutamate – can act on the receptors. Glutamate
has two major families of receptors – one family called ‘ionotropic glutamate receptor’, or ‘iGluR’s, and these
are ion channels activated by glutamate. Pharmacologically, they could be subdivided into NMDA, AMPA, and
kainate types. They’re all cation channels. And, mostly, they allow in sodium and out a little bit of potassium.
However, the NMDA type cation channel also allows in significant quantities of calcium ions, which will be
important later on in the module.
Conversely, there’s another group of receptors that glutamate can act on and that’s the ‘metabotropic
glutamate receptors’, or ‘mGluR’s. These are G-protein coupled receptors in the class ‘C’. Again, these can be
subdivided into ‘Group One’, ‘Group Two’ and ‘Group Three’. Group One contains the mGluR ‘one’ and ‘five’. And
these couple to particular G-proteins called ‘Gq’ and ‘G11’. Group Two include metabotropic glutamate
receptors ‘two’ and ‘three’. And these couple to different G-proteins, ‘Go’ and ‘Gi’. And then the final group –
Group Three – include the metabotropic glutamate receptor ‘four’ and numbers ‘six’ to ‘eight’. And these, again,
all couple to the G-proteins, ‘Go’ and ‘Gi’.
REUPTAKE
Once the neurotransmitter is released and acted on its receptors, then it can be re-uptaken back either into the
neuron – as it shows on the left of this slide – or, indeed, back into glia – in this case, astrocytes, on the right
hand of the slide. As we know, glutamate released into the synaptic cleft, can then diffuse. There are special
transporters – proteins – that specifically take up glutamate back into the neuron. And they’re known as
excitatory amino acid transporters. And they can return the glutamate back into the presynaptic terminal of the
neuron, where it can be repackaged into vesicles and reused.
Conversely, it can be taken up by the glial cells – in this case, astrocytes – and, here, it’s converted into
glutamine by glutamine synthase. The glutamine can then be transported out of the astrocyte and into the
neuron by the glutamine transporter, ‘GlnT’. And that can then be synthesised back into glutamate by
glutaminase. So, you can see there’s quite a complex process of removing glutamate from the synaptic cleft
and recycling it.
DEGRADATION
So, the first ‘D’ is ‘degradation’. Glutamate is quickly removed from synaptic cleft by the excitatory amino acid
transporters and recycled. In astrocytes, it’s converted to glutamine by glutamine synthase. And the glutamine
is transferred back to the neuron, where it’s converted back to glutamate by glutaminase. And again, this can
be reused.
DRUGS
The final ‘D’ covers two areas for this particular neurotransmitter. It indicates, firstly, the ‘drugs’ that act at this
synapse. And these are examples for glutamate, shown on this slide. The receptors at which these drugs react
are the NMDA receptor and the classic example of a drug that does this is ‘ketamine’. This is a dissociative
anaesthetic and a channel blocker at this receptor. ‘Memantine’ is a competitive antagonist at this receptor.
And, furthermore, another recently discovered and approved drug that acts on AMPA receptors is
‘perampanel’. And that’s a competitive antagonist. So, you can see- you can map the drugs that act on the
synapse to this system.
DISEASE
The second subset ‘D’ here is the ‘disease’. And, first of all, we know that some diseases are caused by the
recreational uses of drugs – drug addiction and dependency. And that’s what I’ve put under recreational drugs,
in the top left part of this slide. Some famous drugs, such as PCP and ketamine, are used as recreational drugs
that act on the glutamate system in the brain. There are also some diseases particularly associated with a
glutamatergic system. And that is epilepsy, because the control of the excitability of the brain is partly under the
control of the glutamate system. In terms of function, glutamate is critical to pretty much all CNS functions.
Slide 15:
Once we have gone through all the particulars for that neurotransmitter, we can produce something called a
‘fact sheet’. And this is shown on the slide now. Notice the neurotransmitter is glutamate – so that’s what we’ve
just done.
FACT SHEET
And down on the left-hand side, I’ve given the individual letters – ‘S’, ‘S’, ‘R’, ‘R’, ‘R’ and ‘D’. And against these,
you can put in the specific enzymes, ion channels, receptors etc that are associated with each part for this
neurotransmitter.
And on the right-hand side, you can indicate any drugs that you know of that act at these particular places. And
you can subset the drugs, if you like, as I’ve done here. I’ve indicated, in green, drugs that are clinically used
today.
So, for glutamate, the first ‘S’ is glutaminase. And that’s one of the important enzymes that make it. The second
‘S’ – ‘storage’ – we know the storage is vesicular.
The first ‘R’ is calcium dependent release at the terminal, so that’s release. And then the receptors we know
about for glutamate are split into two major families – ionotropic, which include NMDA, AMPA and kainate, and
then the eight subtypes of metabotropic glutamate receptors, which are G-protein coupled. Reuptake is by the
excitatory amino acid transporter – EAAT. And degradation is by glutamine synthase.
On the right, I’ve indicated two drugs which are clinically useful – ketamine is used, as I said, as a dissociative
anaesthetic and perampanel, which is used in some forms of CNS disorders.
What is ‘en passant’ and what does it relate to?
Release - esp dopamine - And that’s where you have small
release sites that occur all the way down the axon, and these varicosities can release
dopamine all the way down, as the axon travels through tissue,
What does varicosities mean?
the quality or state of being abnormally or markedly swollen or dilated - SUCH AS THE RELEASE SITES FOR DOPAMINE
