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Exam 2 (and 3) - CNS, mental health, renal and liver > CNS neurotransmitters > Flashcards

CNS neurotransmitters Flashcards

1
Q

Is glutamate excitatory or inhibitory?

A

Excitatory

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2
Q

How is glutamate produced?

A

Is an amino acid: can be synthesised though (not diet only), in the pre-synaptic terminal as a bi-product from the Krebs cycle:
- Glucose feeds into the kreb’s cycle
- 𝛼- oxoglutamate intermediate is converted to glutamate via the GABA-T enzyme
- Glutamate can also be produced from the amino acid Glutamine via they glutaminase enzyme.

LOOK AT DIAGRAM

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3
Q

How is glutamate loaded into vesicles and transported?

A

Glutamate is loaded into synaptic vesicles to be stored, ready for release.

  • Glutamate is produces and loaded into synaptic vesicle via the VGLUT transporter
  • This vesicle fuses with the membrane and releases glutamate into the synapse, via Ca2+ dependent exocytosis
  • Vesicles diffuse across the synapse and Glutamate is released.
  • The Excitatory amino acid transporters (EAAT) on neurones and astrocytes take up glutamate from the synapse. In neurons, glutamate can be re-cycled and re-used. In astrocytes, uptake glutamate is converted to glutamine by glutamine synthase. this is stored as Glutamine in astrocytes as a pool of inactivates neurotransmitter.
  • Glutamine can be released out of astrocyte and into neurones via glutamine transporters. Once in neurone, it can be converted back to glutamate via glutaminase enzymes
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4
Q

What are the 2 categories of glutamate receptors?

A
  • Metabotropic glutamate receptors (mGluRs): these are GPCRs which need secondary messengers
  • Inotropic glutamate receptors: these are ligand-gated ion channels. Can be further divided into:
    NMDA receptors
    AMPA receptors
    Kainate receptors
    these all react differently to synthetic analogues but all respond to glutamate (endogenous ligand)
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5
Q

Describe the structure of an NMDA receptor

A

They are assembled from 7 potential subunits encoded by 7 different GluN genes:
GluN1
GluN2A
GluN2N
GluN2C
GluN2D
GluN3A
GluN3B

  • It is a tetrameric complex: Contains 4 of the units above.
  • Is hetero-tetramer: the units have to be different e.g. won’t just be 4 x GluN2As
  • Most common:
    2 x GluN1 and 2 x GluN2 subunits
  • Alternative splicing can affect the GluN1 genes = 8 variants of this gene

Structure of each sub-unit:
Each has:
- N-terminal domain (Extra-cellular)
- Large ligand binding domain- binds agonist- glutamate
- three membrane spanning 𝛼-helical domains (M1,M3,M4)
- A re-entrant loop - M2
- Intracellular c-terminus (Intracellular)
(LOOK at diagram)

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6
Q

What determines the extent and time of desensitisation of NMDA receptors?

A

The sub-units involved
In NMDA receptors, in the presence of glutamate, all channels open and ions move but depending on if the GluN2 subunit is A,B,C,D determines when the channels are deactivated.
A= fastest deactivation
B= similar to A, slightly less
C= Don’t deactivate fast
D= Don’t deactivate fast

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7
Q

What are the 5 major drug binding sites on a NMDA receptor?

A
  • Glutamate (agonist) site
  • Glycine site
  • Polyamine site
  • Mg2+ site- within ion channel pore
  • Channel blocking site
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8
Q

What does a NMDA receptor need for full activation?

A

Each tetramer binds 2 glutamate molecules to become activated and open (or the synthetic agonist, NMDA, endogenous ligand:glutamate).
For full activation though, it requires a co-agonist: glycine- 2 molecules of glycine bind to the GluN1 glycine-binding subunit.
Note, D-serine and D-alanine can also act as co-agonsits.

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9
Q

How does activation by the agonist site work and what drugs target this (NMDA Receptor)?

A

Activation by the endogenous ligand glutamate, or synthetic ligand, NMDA. Requires 2 glutamate molecules to bind and activate and open.
For full activation, it requires a co-agonist: glycine- 2 molecules of glycine bind to the GluN1 glycine-binding subunit.

Drugs to target:
- Competitive antagonists at the glutamate site- blocks the access of agonist or co-agonist
e.g. D-APS- limited drug development though due to conservation of glutamate binding site via NMDAr, AMPAr and Kainate r
- Antagonists at glycine site- block the co-agonist to decrease NMDA receptor activity e.g. Kynurenic acid

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10
Q

How does activation by the Mg2+ site work (NMDA Receptor)?

A

At rest, magnesium ions block the NMDA receptors via plugging the inside of the ion channel pore = ions can’t move through.
When the membrane is depolarised, the magnesium ion block is relieved and they leave the pore, allowing other ions to move through = voltage-dependent channel block.

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11
Q

How does activation by the polyamide site work and what drugs target this (NMDA Receptor)?

A

Polyamine site: The allosteric modulator in the N-terminus.

Cells have a high concentration of polyamines e.g. spermine, spermidine.
These can act at the NMDAr and binding induces a conformational change which leads to enhanced activity of agonist or co-agonists.
e.g. increased glycine or glutamate affinity which increases ion Chanel responses.

e.g. Ifenprodil- binds close to the polyamine site to decrease activity (inhibitory)- makes it harder for the conformational change to occur and for the ion channel pore to be opened.

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12
Q

How does activation by the channel blocking site work and what drugs target this (NMDA Receptor)?

A

This channel blocking site is found within the ion channel pore. Drugs can only access the inside of the iron channel pore when the channel is open. To be open, the channel must be activated, these drugs can then bind and block the pore.
e.g. Ketamine, Phenylcyclidine, Memantine (binds to M2 domain inside channel pore)

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13
Q

What is an example of an allosteric modulator that alters NMDAr activity (NMDA Receptor)?

A

Neurosteroids can have positive or negative allosteric modulator ability and alter the NDMAr activity.
e.g. Pregnenolone sulfate- acts as a positive allosteric modulator at the GLU2NA subunit-containing NMDA receptors

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14
Q

Discuss the structure of an AMPA receptor.

A
  • 4 genes encode different subunits of the AMPA receptor:
    GluA1
    GluA2
    GluA3
    GluA4
  • These 4 subunits come together to form a tetramer.
    This can be a:
    Homotetramer: 4 identical subunits
    Hetrotetramer: mixed subunits
    These subunits can change the properties of the ion channel e.g. opening and sluicing, time of desensitisation and what ions can go through the pore etc
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15
Q

Discuss the structure of a Kainate receptor.

A

Are tetrameric receptors (4 subunits in each): 5 genes encode different sub-units:
GluK1
GluK2
GluK3
GluK4
GluK5

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16
Q

Are NMDA receptors or AMPA receptors permeable to calcium ions and what is the cause of the different permeabilities?

A

NMDA is highly permeable to calcium ions BUT AMPA receptors are impermeable to calcium (only sodium and potassium ions can move through their pore).

The selectivity is due to the amino acid sequence in the M2 domain (the re-entrant loop) has a single aa difference:
- NMDAr: Neutral aa sequence (Asparagine)
- AMPAr: has uncharged aa (Glutamine)
The GluA2 subunit (can only be in AMPAr) undergoes an RNA editing process causing modified mRNA sequence to form a positive arginine amino acid at this position- this decreases the permeability to calcium ions.
This single aa difference, is crucial in controlling the electrical activity of the brain. e.g. in a mouse with a GluA2 subunit with a glutamate reside, they developed seizures due to calcium ion overload.

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17
Q

Discuss the structure of metabotropic receptors.

A

They are GPCRs- 7 transmembrane domains
- large EC N-terminal domain, where glutamate (ligand) binds
- There are 8 sub-types- mGluR1-mGluR8

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18
Q

What are the different group do metabotropic receptors?

A

Group 1:
Includes mGluR1 and m GluR5
- Are coupled to G𝛼Q or G𝛼II, causes activation of phospholipase C = second messenger molecules such as IP3 , diacylglycerol = increased cA2+ intracellular conc.
is an excitatory signalling pathway- Post-synaptic

Group 2+3: divided by sensitivity to an analogues
2: mGluR2 and 3
3: mGluR4, 6, 7, 8
Linked to the inhibitory G-protein, G𝛼I/O = inhibitory to adenylate cyclase = decrease in cAMP
- Pre-synaptic location- is inhibitory

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19
Q

What are examples of drugs that can distinguish between the sub-types of mGluR receptors?

A
  • Antagonists for group 1: Potential for epilepsy, pain, Parkinsons = decrease excitatory responses
  • Antagonists for group 2: prevention of inhibitory regulation of neurotransmitter release = enhances glutamate signals
  • Positive allosteric modulators for group 3: potential for Parkinsons, anxiety - enhance responses of inhibitory glutamate receptors = enhance prevention of NT release ( decreased excitatory responses)
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20
Q

What are EPSPs and EPP?

A

The pre-synaptic cell generates an action potential (goes from -70mV to +50mV). The signal then travels across the synapse. in the post-synaptic cell, the membranes is slightly depolarises = this is the excitatory post-synaptic potential (EPSP) of -70mV to -55mV. EPSP is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential
- End plate potential (EPP): a type of large EPSP (70mV) which activates AP in muscle cells

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21
Q

What are the ESPS generated in the CNS like?

A

In the CNS, the pre-synaptic neurones only generate small ESPS <1mV = this is not enough to generate an action potential in the post-synaptic cell.
Therefore, inputs from many pre-synaptic neurones are required to generate an AP- this needs to reach a threshold potential. Depolarisation eventually reaches threshold potential for firing at 10mV.
Not all inputs are the same, some can be excitatory and some inhibitory so the overall response is the result of the net effect of these inputs.
Can also be dependent on types of receptor present on the post-synaptic cell e.g. if inotropic glutamate receptors, tends to be an excitatory synapse.

22
Q

What are the two types of synapse?

A

Type 1:
- Glutaminergic
- Excitatory
- Round synaptic vesicles
- Large post-synaptic density
- Wide synaptic cleft
- Typically contact at dendritic spines

Type 2:
- GABAnergic
- Inhibitory
- flattened (oval) synaptic vesicles
- Less post-synaptic density
- Narrow synaptic cleft
- Typically contact at soma or cell body or dendritic shaft.

23
Q

What is a post-synaptic density and how do the receptor sub-units interact with it?

A

A cluster of ion channels and proteins/receptors on post-synaptic cell to receive signals. Receptors are clustered by lots of regulatory proteins into areas called a “postsynaptic density”
* A typical PSD is 350nm in diameter and can contain 20 NMDAR (blue) and 10-50 AMPAR (green)

  • It involves a lot of a protein called PSD-95, this has a PDZ domain needed for protein-protein interactions e.g. interacts with NMDArs to localise and hold them in place.
  • The PSD doesn’t directly bind to the AMPAr but binds to a protein called TARP which regulates AMPArs.
  • mGluRs are located on the edge of the PSD and interact with the Homer PD2 protein to keep the receptor docked
24
Q

What is the EPSC?

A

Excitatory post-synaptic current (ESPC):
AMPAr and NMDA receptors are found in the post-synaptic density and both respond to glutamate in the synaptic cleft.
AMPAr = fast
NMDAr = slow

can use pharmacological tools to identify which channels are active and when:
Can give NMDAr antagonists e.g. DAP5:
- The response is not much different whether DAP5 was present to not showing NMDArs are not involved in this response.
At this voltage NMDAr is blocked by Mg2+ so prevents any ion flow. As the membrane is depolarised to -40mV = NMDAr dependence- there is a difference in current when with and without DAP5
At +20mV = time difference between AMPAr and NMDAr activation. NMDAr are activated and reactivated slower than AMPAr

25
Q

What is synaptic plasticity?

A

How transmission can be altered over time and causes long-term changes in connectivity between neurones.

26
Q

What is LTP?

A

Longterm potentiation (LTP)- a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron. LTP is involved in learning and memory (hippocampus).

27
Q

Discuss the process of long-term potentiation.

A
  • After conditioning train mimics frequent activity or repetitive firing of a neurone.
  • More glutamate release from the pre-synaptic cell into the synapse leads to more receptors being activated = sufficient depolarisation of post-synaptic cell membrane by AMPAr which allows un-blocking of NMDA receptors.
  • As the membrane potential increases, there is an unblocking of NMDArs by magnesium ions and so glutamate can bind and activate these receptors.
  • This allows high levels of calcium ions influx into the post-synaptic cell and activates various signalling pathways and uncreased expression of AMPA receptors in the post-synaptic density.
  • also activation of kinases e.g. protein kinase C and CAM Kinase which phosphorylates the AMPA receptor to facilitate AMPAr activation.
  • calcium ions activate nitric oxide synthase enzyme, NO is produced which acts as a retrograde messenger. this acts on pre-synaptic cell to enhance neurotransmitter release into the synapse
  • this leads to a strengthened signalling loop and can induce long-term genes expression changes.
  • Additionally, activation of matabotropic glutamate receptors which further enhance intracellular calcium ion signals.

GO OVER WTF

28
Q

What receptor type has risk of excitotoxicity and what issues can this cause>

A

Excitotoxicity is relevant to NMDA receptors as they have high calcium ion permeability.
- high concentrations of glutamate in the extra-cellular space can lead to calcium ion overload and therefore toxicity which causes neuronal cell death.
- Excitotoxicity is thought to be a major factor in iscahemic brain damage and in neurodegenerative diseases

29
Q

What is the main inhibitory neurotransmitter in the CNS?

A

GABA
20% of CNS neurones are GABA-ergic and are short inhibitory interneurons (link other neurones)

30
Q

What must neurones express to be GABA-ergic?

A

They must express the GAD enzyme (Glutamic acid decarboxylase) which catalyses the conversion of glutamate to GABA.
- If they don’t express GAD, the neurones can’t metabolise glutamate to GABA.

31
Q

How is GABA synthesised?

A
  • Via the Krebs cycle - Glutamate to GABA via the GAD enzyme (Glutamic acid decarboxylase)
  • Can also be metabolised by GABA-T ( GABA-Transaminase) to succinct semialdehyde. This can be entered back into the Krebs cycle- ‘GABA Shunt’ = therefore is a closed loop pathway to preserve GABA.
32
Q

How is GABA packaged and released?

A
  • GABA is packed into vesicles via a vesicular transporter
  • This is released in response to calcium-dependent exocytosis.
  • GAB acts in receptors on the post-synaptic neurone
  • GABA can be recycled via GABA transporters on pre-synaptic terminal
  • GABA can also be taken up by astrocytes via a GAT-3 transporter.
33
Q

What drugs can affect GABA transport and metabolism?

A
  • Guvacine and Tiagabine- act on GABA transporters to increase the concentration of GABA in the synapse = reuptake inhibitors
  • Vigabatrine- acts to inhibit GABA transaminase = prevents GABA breakdown and therefore increases concentration
34
Q

What receptors does GABA act on?

A
  • Inotropic receptors- GABAa (ligand-gated ion channels)
  • Metabotropic- GABAb (GPCRs)
35
Q

Discuss the structure of the GABAa receptors?

A

They are Ligand-gated anion channels (-ve)- is only selective for Cl- ions

Structure:
- is pentameric- made up of 5 subunits
- is heteromeric- made up of different subunits..
There are 19 identifies subunits including:
6 x 𝛼-subunits
3 x β-subunits
3 x 𝜸-subunitss

The most common pentamer is 2𝛼, 2β and a 𝜸 subunit.
60% of receptors are 𝛼1β2ᵞ2
- 2 alpha subunits can’t go next to eachother

Structure of each subunit: on another flashcard so put together in an exam Q

36
Q

Discuss the structure of a GABAa subunit.

A
  • 4 full membrane-spanning transmembrane domains
  • Long extra-cellular N-terminus
  • Short extra-cellular C-terminus
  • Long intracellular loop between TM3 and TM4
  • TM2 lines the ion channel pore.

PLEASE LOOK AT THE DIAGRAM.

37
Q

What are the 5 drug binding sites of a GABAa receptor?

A
  • GABA site- agonist
  • Benzodiazepine site
  • Modulatory site- barbituate
  • Steroid site
  • Picrotoxin site (Channel blocking)

Ethnol also binds to the GABAa receptor and increases its activity.

38
Q

How does activation by the GABA agonist binding site work (GABAa Receptor)?

A
  • Binding of GABA induces a conformational change allowing the ion channel pore to open and iOS can flow
  • There are 2 GABA binding sites per pentameric complex and are located between the alpha and the beta subunit interface.

Other chemicals that can also bind here:
- Muscimol- GABA agonist prom psychoactive mushrooms which binds as a potent agonist and opens the ion channels
- Bicuculline: competes with GABA and blocks this site (competitive antagonist), can cause convulsions.

39
Q

How does activation by the benzodiazepine binding site work (GABAa Receptor)?

A

These are drugs that selectively enhance the effects of GABA- positive allosteric modulators. These don’t bind to the GABA site but bind with high affinity to the BDZ site between the alpha and gamma subunits.
- Not all of the sub-units provide this benzodiazepine site e.g. alpha-4 and alpha-6 can’t

Drugs that act here:
e.g. Valium and diazepam- used in anxiety, epilepsy, anaesthesia and sleep

40
Q

How does activation by the Barbiturates binding site work (GABAa Receptor)?

A

These drugs are used in sleep, anxiety (not much now)
- Drugs that bind here increase ligand binding to the BDZ and GABA sites to increase the channel opening time and enhancing activity of GABAa ion channels e.g. pentobarbital

41
Q

How does activation by the steroid binding site work (GABAa Receptor)?

A

Neurostreoids (metabolites of steroid hormones) are endogenous modulators that enhance the affects of GABA
- they act on transmembrane regions of the alpha-subunits- M1 and M2
e.g. Allopregnanolone

42
Q

How does activation by the channel blocking binding site work (GABAa Receptor)?

A

Binding inside the ion channel pore- this requires opening of the channel to gain access to and bind in the pore and block the channel
e.g. Picrotoxin- blocks passing og ions through the channel

43
Q

Discuss the structure of GABAb receptors.

A

Metabolic GPCRs
- Are class C GPCRs:
large N-terminal domain which contains the agonist binding site.
- is couples to the G𝛼I/o protein
- They assemble as dimers in the membrane:
there are 2 forms: GABAb1 and GABAb2

  • signalling through G𝛼I/o on GABAb receptors = inhibition of voltage gates calcium ion channels = decrease in NT release from the pre-synaptic neurones.
  • in post synaptic neurone it causes activation of k+ channels = increase hyper polarisation and increased difficulty to fire an action potential
44
Q

Describe the synthesis or serotonin?

A

Tryptophan is a precursor derived from the diet.

Is converted to 5-hydroxytryptophan by tryptophan hydroxylase

This is then converted to 5-hydroxytryptamine (serotonin) by DOPA decarboxylase.

this is then packaged into vesicles and used as a neurotransmitter.
However, it can also be degrades: by monoamine oxidase and then aldehyde dehydrogenase to 5-hydroxyindoleacetic acid which is excreted.

45
Q

What facilitates the loading of serotonin into vesicles?

A

Vesicular monoamine transporter (VMAT)

46
Q

What permits the re-uptake of serotonin into the pre-synaptic neurone?

A

SERT- uptake transporter

47
Q

Where do the serotonergic neurones lie?

A

The cell bodies of these neurones line in the Raphe nucleus and project to many areas of the brain

48
Q

What is seratonin involved in?

A

Sleep
appetite
pain
thermoregulation
mood

49
Q

Discuss the different serotonin receptors?

A

There are 14 known serotonin receptors- all BUT one are GPCRs. This one is a ligand-gated ion channel (5HT-3).

Seven different types:
- 5HT3-ligand gates- one above
GPCRs:
- 5HT1 receptors ( 1A,1B,1D,1E,1F). These are all couples to G𝛼I/o and cause inhibition of adenylate cyclase and decrease cAMP.
- 5HT-2 receptors (2A,2B,2C)- Couples to G𝛼q/II- regulate the activity of phospholipase C- regulation of 2nd messenger molecules e.g. IP3, diacyl glycerol = release of calcium ions = excitatory
- 5HT-2, 5HT-5a, 5HT-6 and 5HT-7 are all couples to G𝛼Sa and stimulate adenylate cyclase to increase production of cAMO.

50
Q

Discuss the pharmacology of the serotonin receptors.

A
  • 5-HT2: used in migraine prophylaxis. Are excitatory do use antagonists to block their action for a therapeutic effect e.g. ketanserin, pizotifen
  • Ergotamine binds to 5HT2 antagonist
  • 5-HT2 receptors cause smooth muscle contraction via their excitatory activation of phospholipase c = increase ca2+ ion
  • 5-HT3 receptors- found in PNS and CNS and have a major involvement in the vomitting reflex. 5-HT3 antagonist e.g. ondansetron (anti-emetic)

Exam 2 (and 3) - CNS, mental health, renal and liver (23 decks)

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