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PHYS - NEURO > 3. GLUTAMATE > Flashcards

3. GLUTAMATE Flashcards

1
Q

What are neurotransmitters?

A
  • Neurotransmitters are chemical messengers hat transmit signals from a neurone to a target cell
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2
Q

What is the process of synaptic transmission?

A
  1. Neurotransmitter synthesised at nerve terminal or cell body
  2. Neurotransmitter packaged into vesicles
  3. Arrival of action potential causes depolarisation
  4. Voltage gated Ca2+ channels open
  5. Neurotransmitter is released via exocytosis & binds to receptors on the post-synaptic membrane
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3
Q

What is glutamate?

A
  • Glutamate is the major excitatory neurotransmitter in the CNS
  • Approx half of brain synapses = glutamate mediated
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4
Q

How is glutamate synthesised?

A
  • Glutamate can be synthesied but it’s mostly converted from the precursor Glutamine
  • Glutamine –> Glutamate by the enzyme GLUTAMINASE
  • GLUTAMINASE changes the NH3 group into a carboxyllic acid, changing glutamine into glutamate
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5
Q

What enzyme catalyses the conversion of glutamine into glutamate?

A
  • GLUTAMINASE

- Glutamine -> Glutamate

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6
Q

Describe the transport & storage of glutamate in vesicles

A
  • Glutamate is packaged into vesicles by VGLUT (vesicular glutamate uptake transporters)
  • The transport of glutamate into vesicles is driven by the movement of H+ out of the vesicle
  • The inside of the vesicle is acidic, which is maintained by the H+ pump. H+ moves out of the vesicle, down the conc gradient
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7
Q

What transporters are involved in the re-uptake of glutamate & what do they do?

A
  • Glutamate is released into the synaptic cleft by exocytosis
  • EAAT (Excitatory amino acid transporters) are located on neurones & glial cells
  • The EAAT are involved in re-uptake of glutamate. They take up glutamate from the synaptic cleft to be converted into glutamine
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8
Q

What enzyme degrades glutamate into glutamien?

A
  • Once glutamate is taken up into glial cells by EAAT it’s converted to glutamine by GLUTAMINE SYNTHETASE
  • Glutamate –> Glutamine
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9
Q

Describe the transport of glutamine out of cells after re-uptake?

A
  • Once glutamate, has been converted to glutamine in the glial cell it will be transported out & back into the neurone
  • Glutamine is transported out of the glial cell by SN1
    (SYSTEM N TRANSPORTER)
  • The glutamine will then be transported into the neurone by SAT2 (SYSTEM A TRANPORTER 2)
  • The whole process is known as the glutamate-glutamine cycle
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10
Q

What are the two main families of glutamate receptor?

A
  1. IONOTROPIC (LIGR)

2. METABOTROPHIC (G-PROTEIN COUPLED)

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11
Q

What 3 ionotropic receptors does glutamate bind to?

A
  1. AMPA
  2. NMDA
  3. KAINATE
    - The ionotropic receptors are all located post-synaptically & allow the influx of Na+ & the efflux of K+. NMDA also allows the influx of Ca2+
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12
Q

What are the 4 sub-units of the AMPA receptor & the most common configuration?

A
  1. GluA1
  2. GluA2
  3. GluA3
  4. GluA4
    - Most common = 2GluA2 with either 2GluA3 or A4 or A1
    - GluA2 is constant but the others are variable
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13
Q

What’s the importance of the GluA2 sub-unit in AMPA receptors?

A
  • The GluA2 sub-unit is constant

- The presence of the GluA2 prevents Ca2+ & therefore prevents the mediated excitotoxicity resulting from it

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14
Q

What are the properties of the AMPA receptor?

A
  • The AMPA receptor has 4 glutamate binding sites
  • 2 binding sites need to be occupied in order for the ion channel to open
  • Allows: Na+ influx & K+ efflux
  • Found post-synaptically
  • Forms a hetero-tetramer
  • Current produced by AMPA will be greater if more binding sites are occcupied
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15
Q

What are the 3 sub-units for the NMDA receptor & he most common configuration?

A
  1. GluN1
  2. GluN2
  3. GluN3
    - Most common: 2GluN1 & 2GluN2
    - The 2GluN2 can be replaced with 2GluN3
    - All binding sites need to be occupied for an ion channel to open
    - GluN3 sub-units are non-functional & are inhibitory to receptor function
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16
Q

What are the properties of the NMDA receptor?

A
  • The NMDA receptor allows for a Ca2+ influx aswell as the influx of Na+ & efflux of K+
  • All binding sites need to be occupied for the ion channel to open
  • NMDA receptors are both ligand & voltage gated channels
  • Ligand: Both Glutamate and Glycine or D-Serine need to bind
  • Voltage: NMDA receptors have a Mg2+ block which blocks the ion channel. Once there’s sufficient depolarisation of the membrane, the Mg2+ block dissociates allow the influx of cations
17
Q

What ligands bind to the NMDA receptors & what sub-unit do they bind to?

A
  • Glutamate = binds to the GluN2 sub-unit

- Glycine or D-serine = bind to GluN1 sub-unit

18
Q

What are the 5 sub-unit types for Kainate receptors?

A
  1. GluK1
  2. GluK2
  3. GluK3
  4. GluK4
  5. GluK5
    - Glutamate binding is required for ion channel opening, but it’s not well understood
19
Q

What are the properties of Kainate receptors?

A
  • Kainate receptor are found on the post-synaptic membrane
  • GluK1 -GluK3 = from HOMOMERS
  • GluK4 & GluK5 form HETEREOMERS with GluK1 - GluK3
  • Limited distribution in the brain compared to NMDA & AMPA receptors
20
Q

What are the three groups of metabotropic glutamate receptors?

A
  1. GROUP 1 (POST-SYNAPTIC)
  2. GROUP 2 (PRE-SYNAPTIC)
  3. GROUP 3 (PRE-SYNAPTIC)
    - Metabotrophic receptors can have both inhibitory & excitatory effects
21
Q

What sub-types make up the three groups of metabotropic glutamate receptors?

A
  • There are 8 sub-types in total: mGlu1 - mGlu8
  • GROUP 1 = mGlu1 & mGlu5
  • GROUP 2 = mGlu2 & mGlu3
  • GROUP 3 = mGlu4, mGlu6, mGlu7, mGlu8
22
Q

Describe the properties of Group 1 glutamate receptors?

A
  • Group 1 receptors are located on the post-synaptic membrane
  • Group 1 receptors are coupled to Gq, so they’re positively linked to phospholipase C
  • Phospholipase C converts PIP2 -> IP3 & DAG leading to an increase in Ca2+
  • Group 1 receptors are important for long-term potentiation & synaptic plasticity
23
Q

Describe the properties of Group 2 & 3 glutamate receptors?

A
  • Group 2 & 3 are located on the pre-synaptic membrane
  • Group 2 & 3 receptors are Gi/o coupled, so they’re negatively linked to adenylate cyclase leading to decerased cAMP formation & therefore decreased Ca2+
  • Inhibition of neurotransmitter release
24
Q

Describe the dimerisation of metabotropic glutamate receptors?

A
  • Can form HOMOMERS with each other e.g mGlu5& mGlu1

- Can from HETEROMERS with each other or other classes of receptor such as 5HT

25
Q

Define depolarisation

A
  • The membrane potential is displaced towards a more positive value
26
Q

What are EPSCs & how do they differ between the ionotropic receptors?

A
  • Deplarisation generates EPSCs - excitatory post-synaptic current. EPSCs represent the flow of ions & the change in current across the post-synaptic membrane
  • EPSCs generate EPSPs which are excitatory post-synaptic potentials
  • AMPA = generate a large EPSC & are the primary mediators of neurotransmission
  • NMDA & Kainate = slow & longer EPSC. Low conductance (NMDA = due to Mg2+ block)
27
Q

What is excitotoxicity?

A
  • Excitotoxicity is a pathological process by which excessive excitatory stimulation results in neuronal cell death & damage
28
Q

How can deficits in the VGLUT cause excitotoxicity|?

A
  • A missing or malfunctioning VGLUT means that glutamate cannot be transported to vesicles, instead it accumulates in the cytosol of the pre-synaptic membrane
  • Normally EAAT transport glutamate back into the cell for re-uptake, but the accumulation of glutamate in the pre-synaptic neurone changes the direction of glutamate transport
  • EAAT then transport glutamate out of the neurone into the cleft. The glutamate then activates the post-synaptic membrane without a stimulus or depolarisation
  • Glutamate binding leads to an excessive influx of Ca2+, causing glutamate mediated excitotoxicity (neuronal cell death & damage)
29
Q

What are the consequences of glutamate-mediated excitotoxicity?

A

. Oxidative stress

  1. Mitochondrial damage
  2. Apoptosis
    - Further complications can lead to Alzheimer’s or stroke
30
Q

Describe the link between Alzheimer’s & glutamate-mediated excitotoxicity?

A
  • Alzheimer’s is a neurodegenerative disease that is characterised by neuronal cell death in the hippocampus which is associated with memory
  • There’s an over-activation of NMDA receptors, leading to excessive Ca2+ influx resulting in excitotoxicity such as neuronal cell death
31
Q

How can Alzheimer’s caused by glutamate mediated excitotoxicity be treated?

A
  • Memantine is an NMDA receptor antagonist which can block the NMDA receptor preventing Ca2+ influx & therefore prevent the excitotoxicity resulting form it
32
Q

Define long-term potentiation

A
  • Long-term potentiation refers to the consistent strengthening of synapses due to repeated patterns of activity. The strength of of the synaptic transmission increases
  • LTP underlies learning & memory
  • LTP is a type of synaptic plasticity
33
Q

What are the five steps of long term potentiation?

A
  1. Glutamate binds to AMPA receptors causing an Na+ influx, resulting in depolarization
  2. Sufficient depolarisation of the membrane results in the NMDA receptors opening & the Mg2+ block dissociates
  3. NMDA receptors channel opening leads to Ca2+ & Na+ influx
  4. Ca2+ acts as a secondary messenger, activating Calmodulin Kinase (CamKII) & Protein Kinase C (PKC)
  5. PKC & CAMKII trigger a series of reactions which lead to new AMPA receptors being expressed/inserted onto the post-synaptic membrane
  6. More AMPA receptors = increased sensitivity of the post-synaptic membrane to glutamate & increases ion channel conductance

PHYS - NEURO (18 decks)

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