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Neuro > Glutamate > Flashcards

Glutamate Flashcards

1
Q

Summarise the function of neurotransmitters

A

From the vesicles fuse to the membrane and are released via exocytosis and diffuse across the synaptic cleft

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2
Q

What is neurotransmission?

A

The fundamental process that drives information transfer between neurons and their targets

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3
Q

What are neurotransmitters?

A

Chemical messengers that transmit signals from a neuron to a target cell across a synapse

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4
Q

Criteria for a neurotransmitter

A
  1. To be synthesised and stored in the presynaptic neuron
  2. Released by the presynaptic axon terminal upon stimulation
  3. Produce a response in the postsynaptic cell
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5
Q

Why are neurotransmitters synthesied and stored in the presynaptic neuron?

A

To be released fast so a readily available pool is needed

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6
Q

What are the two types of neurotransmitter?

A

Ionotropic and Metabotropic

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7
Q

What are the major central neurotransmitters?

A
  • Acetylcholine that acts on nicotinc receptors and muscarinic receptors
  • Glutamate
  • GABA
  • Glycine
  • Monoamines
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8
Q

What is glutamate?

A

A major excitatory neurotransmitter in the central nervous system

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9
Q

How is glutamate formed?

A

Glutamine is converted to glutamate via the enzyme glutaminase that is phosphate activated.

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10
Q

What enzyme converts glutamine to glutamate?

A

Glutaminase

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11
Q

Where is glutamate synthesised?

A

In the pre-synaptic nerve terminals

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12
Q

What transporter puts glutamate into vesicles?

A

vesicular glutamate transporter (v-glut)

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13
Q

How does VGLUT work?

A

It counter transports with H+ to drive glutamate entry into vesicles.

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14
Q

How much glutamate is stored in the vesicles compared to cytosol?

A

Estimated that there is 10(4) higher concentration of glutamate in vesicles than in the cytosol

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15
Q

What are the 3 ionotropic glutamate receptors?

A

AMPA receptors activated by AMPA
NMDA receptors activated by NMDA
Kainate receptors activated by kainic acid

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16
Q

What is the influx and efflux of the ions in AMPA, NMDA and kainate receptors?

A

Influx
AMPA - Na+
NMDA - Na+ Ca2+
Kainate - Na+

Efflux
AMPA - K+
NMDA - K+
Kainate - K+

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17
Q

Mechanism of Action Potential

A
  1. Resting state: At -70mV in a neuron, 3Na+/2Na+ pump.
  2. Depolarisation: Activation of a stimulus results in depolarisation of the neuron
  3. Rising phase of the action potential: Na+ channels open and more sodium enters the cell.
  4. Falling phase of the action potential: Na+ close and K+ open; K+ efflux from the cell. Membrane potential becomes more negative
  5. Undershoot: K+ channels are too slow to close therefore, there is an action potential that arrives at the presynaptic neuron. This triggers the release of calcium from VGCC (on pre-synaptic neuron). This triggers the release of synaptic vesicles containing neurotransmitters by exocytosis
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18
Q

What type of receptor is AMPA?

A

A glutamate ionotropic receptor

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19
Q

Four subunits of AMPA

A

GluA1
GluA2
GluA3
GluA4

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20
Q

Common subunits of AMPA

A

2 GluA2 subunits bind and then a mixture of either 2GluA1, 3 or 4 will bind.

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21
Q

What type of structure does the AMPA receptor form?

A

A hetero-tetrameric structure - dimer of dimers.

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22
Q

How many binding sites does the AMPA receptor have?

A

It has four orthosteric binding sites.

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23
Q

How many binding sites need to be occupied to open the AMPA channel?

A

When two of the binding sites are occupied. The current increases as more binding sites are occupied.

24
Q

What prevents Ca2+ flow from entering the cell?

A

Presence of GluA2 subunits prevents Ca2+ flow from entering the cell, this is a protective measure of excitotoxicity.

25
Q

What type of receptor is NMDA?

A

Ionotropic

26
Q

What are the three subunits of NMDA receptors?

A

GluN1 (or NR1)
GluN2 (or NR2)
GluN3 (or NR3)

27
Q

What are the most common subunits for NMDA receptors?

A

2 GluN1 subunits and 2 GluN2 (or GluN3)

28
Q

What type of subunits are the GluN3 subunits?

A

They are inhibitory to the NMDA receptor function

29
Q

What type of ion channels are the NMPA receptors?

A

Ligand and voltage gated

30
Q

Which ligands bind to the NMPA receptor and which subunits do they bind to?

A

Glutamate binds to the GluN2 subunit.

Glycine or D-serine binds to the GluN1 subunit

31
Q

How are the NMPA receptor also voltage gated?

A

The ligand binds to the receptor and when there is a depolarisation event, the Mg2+ block which is at the resting potential membrane moves to allow the ions through.

32
Q

How many binding sites need to be occupied for the channel to open?

A

All sites must be occupied.

33
Q

What type of structure is the NMDA receptor?

A

Heterotetrameric

34
Q

What is synaptic plasticity?

A

The ability of the neuron to change and adapt

35
Q

What is long term potentiation?

A

A type of synaptic plasticity which is the strengthening of the connection between two neurons.

36
Q

What is important for synaptic plasticity?

A

Glutamate

37
Q

Why is glutamate important for synaptic plasticity?

A
  • It binds to the receptors causing an influx of sodium into the cell.
  • It removes the Mg block, allowing sodium and calcium into the cell.
  • Leads to receptor trafficking meaning more AMPA receptors are added to the membrane
  • More sodium influx which can activate CamKII.
  • CamKII phosphorylates the receptors to increase sodium influx.
  • This increases the ionic conductance of these receptors therefore, more Na+ and Ca2+ is entering the cell.
  • This activates long-term potentiation where over time there is synaptic strengthening.
  • NMDA receptors will not work without the activation of sodium from the influx from the AMPA receptors.
  • This process underlies learning and memory essentially.
  • Increased EPSP triggers the action potential.
38
Q

What is receptor trafficking?

A

When more receptors are added to the membrane causing a high influx of ions

39
Q

What are glutamate kainate receptors?

A

Originally thought to be AMPA receptors, before being discovered as Kainite receptors.

40
Q

What are the five subunit sites of Kainate receptors?

A 
GluK1 
GluK2 
GluK3
KA1
KA2
41
Q

What type of structure do kainate receptors form?

A

Tetrameric

  • GluK1 - 3 can form homomers or heteromers
  • GluK4 and 5 only heteromers with GluK1-3 subunits
42
Q

What type of channel is the Kainate receptor?

A

It is a ligand gated ion channel.
- Glutamate binds for the channel to open but this mechanism is not well understood. Limited distribution in the brain. Function is less understood than AMPARs and NMDARs

43
Q

What are metabotropic receptors?

A

G-protein coupled receptors

44
Q

Structure of metabotropic receptors

A
  • Venus flytrap domain
  • Cysteine rich domain
  • C-terminal domain
  • 7-transmembrane domain
45
Q

What are the subtypes of metabotropic glutamate receptors?

A

Group 1 containing mGlu 1 and 5
Group 2 containing mGLu2 and 3
Group 3 containing mGlu4, 6 7 and 8

46
Q

Where are the group 1 glutamate receptors located and what is there mechanism of action?

A

Located post-synaptically. Coupled to Gq leading to an elevation in Ca2+.

47
Q

Where are group 2 glutamate receptors located and what is there mechanism of action?

A

Located pre-synaptically. coupled to Gi/o which inhibits adenylyl cyclase inhibiting ATP to cAMP reducing cAMP formatino

48
Q

Where are group 3 glutamate receptors located?

A

Located pre-synaptically.

49
Q

What type of dimers do metabotropic glutamate receptors form?

A

Homomers
Heteromers e.g. mGlu1 and mGlu5
Heteromers e.g. mGlu2 and serotonin (5-HT2A)

50
Q

Which transporters reuptake glutamate?

A

Excitatory amino acid transporter (EAAT)

51
Q

Where are AMPA, MGlu2, MGlu8 and MGlu5 found on the synapse?

A

AMPA - post synaptically
MGlu2 - pre-synaptically
MGlu5 - postsynaptically
MGlu8 - pre-synaptically

52
Q

What is excitotoxicity?

A

The pathological process by which excessive excitatory stimulation can lead to neuronal damage and death.

53
Q

What happens during glutamate-mediated excitotoxicity?

A
  • VGLUT transporters will stop working and they are important for getting NT into vesicles.
  • This means NT glutamate will build up in the cytosol.
  • The EAATs will reverse their function. Normally, glutamate will move from a high concentration in the synaptic cleft to the cytosol.
  • However, in this situation there will be movement of the neurotransmitter from the cytosol into the synaptic cleft.
  • When there is excess in the cytosol, it will bind to AMPA receptors to remove the magnesium block and leading to calcium influx via the NMDA receptors.
  • There is excessive calcium release into the neuron.
54
Q

What happens if there is excessive Ca2+?

A

Mitochondrial damage
Oxidative stress
Apoptosis

55
Q

Which diseases is excitotoxicity linked to?

A

Stroke
Autism
Alzheimer’s disease

56
Q

What is the link between glutamate mediated excitotoxicty and Alzheimer’s disease?

A

Cause shrinkage in the hippocampus which is important in memory.
This is caused by cell death.

57
Q

What drug is used to alleviate the symptoms of Alzheimer’s?

A

Memantine is an antagonist which blocks the NMDA receptor stopping the excess release of calcium. By targeting the NMDA receptors, the symptoms can be alleviated.

Neuro (20 decks)

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