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A PA20023 > Glutamate > Flashcards

Glutamate Flashcards

1
Q

What is glutamate

A
  1. The Main excitatory transmitter in the CNS
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2
Q

What type of receptor does glutamate bind to

A
  1. Amino acid receptor

2. Activates a large family of receptors

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3
Q

What is glutamate synthesised from

A
  1. Glutamine
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4
Q

How is glutamate action terminated

A
  1. Action terminated- Reuptake by the Excitatory Amino Acid Transporters (EAAT)
  2. Aspartate and N-acetylaspartyl glutamate (NAAG) may also play a role
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5
Q

Describe the process of glutamine synthesised

A
  1. Glutamine is exported out of glial cells by glutamine transporters
  2. Glutamine transporters are proteins inserted into cell membrane that are specific for transporting glutamine
  3. Glutamine transporters present on nerve terminals transport glutamine into presynaptic nerve terminal
  4. At mitochondria it meets phosphate activated glutaminase which converts it to glutamate
  5. Glutamate transported into synaptic vesicles by vesicular transporter
  6. When nerve terminal is depolarised the vesicles fuse with membrane releasing glutamate into synapse
  7. Glutamate acts at postsynaptic receptors
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6
Q

What are glial cells

A
  1. Glial cell- non neuronal but involved in function of brain
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7
Q

How is glutamate recycled

A
  1. Recycled back into nerve terminals
  2. Taken up by EAAT
  3. Some is taken up into glial cells where glutamine synthase converts glutamate back into glutamine
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8
Q

Are glutamate receptors ionotropic or metabotropic

A
  1. Can be both
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9
Q

Describe ionotropic glutamate receptors

A
  1. 3 classes
    - NMDA
    - AMPA
    - KA
  2. Subunits for each class
  3. Specific agonists which activate receptors give the name to the ionotropic glutamate receptor
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10
Q

Describe metabotropic glutamate receptors

A
  1. Split into 3 groups
  2. Group I - Stimulate IP3 and Ca2+
  3. Group II- Decrease CAMP
  4. Group III- Decrease CAMP
  5. Divided into groups based on G-protein coupling mechanism and downstream intracellular signalling pathway that is activated
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11
Q

How does glutamate bind to so many receptors

A
  1. It is not a rigid molecule
  2. Different constituents can rotate along two different axes
  3. Can adopt different conformations
  4. Rotates about the alpha-beta and beta-gamma bonds
  5. Nine ‘rotamers’ are possible
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12
Q

Describe structure of ionotropic glutamate receptor

A
  1. Subunits have 4 membrane segments
  2. 1, 3 and 4 are trans-membrane segments
  3. 2 does not span the membrane (p-element)
  4. 4 subunits to a receptor (tetrameric)
  5. P-elements face inward and form channel.
  6. Subunits differ in structure
  7. Subunit composition determines properties
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13
Q

Describe AMPA receptor structure

A
  1. Homomeric- all made up of same subunits
  2. Heteromeric – One different subunit inserted
  3. Has different amino acid sequence and properties
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14
Q

Describe NMDA receptor structure

A
  1. No homomeric
  2. Heteromeric- must always have GluN1
  3. Any combination of the other subunits
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15
Q

Describe AMPA

A
  1. AMPA = alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
  2. Ligand gated ion channel
  3. Permeable to Na+ in and K+ out
  4. Ca2+ if no GluA2 subunit
  5. fast excitatory transmission
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16
Q

What are agonists of AMPA

A
  1. glutamate,
  2. AMPA- most potent which is why it is called AMPA receptor
  3. KA
17
Q

What are the antagonists of AMPA

A
  1. NBQX (competitive)

2. GYKI 53655 (non-competitive)

18
Q

Describe NMDA receptor

A
  1. NMDA = N-methyl-D-aspartate
  2. Pass Na+, K+ and Ca2+
  3. Voltage and ligand gated
    - Voltage sensing- key to function
  4. 1 GluN1 subunit plus 3 GluN2A-D subunits
    - GluN1 is obligatory
  5. Slow and long lasting
19
Q

What is needed along with glutamate to activate NMDA receptor

A
  1. glycine/serine co-agonist
  2. must be bound in order for glutamate to activate receptors
  3. plentiful supply in brain
20
Q

What are the agonists of NMDA receptors

A
  1. NMDA
  2. glutamate
  3. aspartate
21
Q

What are the antagonists of NMDA receptors

A
  1. 2-AP5, CPP (competitive);

2. PCP, Ketamine, MK801 (non-competitive)

22
Q

What gives the different time courses of postsynaptic EPSP

A
  1. glutamate binds both kinds of receptors at most synapses
  2. The different properties of AMPA (fast and short lasting) and NMDA (slow and long lasting) receptors gives a fast and slow time course to the postsynaptic EPSP
23
Q

Describe dual gating of NMDA receptors

A
  1. glutamate alone - no current flows as Mg2+ blocks channel
  2. depolarisation relieves Mg2+ block- requires change in voltage
  3. Ca and Na flow through channel
  4. large slow depolarization
  5. so – NMDA receptors need agonist + depolarisation to work
  6. thus, they can act as transmitter and voltage sensors
  7. Mg-dependent gating is very important in synaptic plasticity, learning and memory
24
Q

Describe metabotropic glutamate receptors

A
  1. mGluRs
  2. GPCRs
  3. 7-transmembrane regions
  4. Not involved in fast excitation
  5. Slow, neuromodulatory role
  6. Many types, connected to different second messenger systems
25
Q

Describe mGluR actions with ion channel

A 
Channels normally allow Ca++ in 
1. Glutamate activates mGluR
2. Leads to Ca-channel closure - reduced Ca++ influx
3. Controls transmitter release
Channels normally allow K+ out
1. Glutamate activates mGluR
2. Leads to K-channel closure - reduced K-efflux
3. Leads to slow depolarization
26
Q

How can mGluR cause release of Ca2+

A
  1. Activation of intracellular enzyme
  2. Initiation of second messenger cascade
  3. Ca2+ release from intracellular stores
  4. Multitude of effects
  5. Further enzyme activation
  6. Opening/closing of ion channels
  7. Modulation of postsynaptic excitability
  8. Very important in excitotoxicity and neurodegeneration
27
Q

Roles of different mGluRs

A
  1. mGluR1 and mGluR5 postsynaptic produce slow depolarisation, release Ca2+ from intracellular stores
  2. mGluR2, 3, 4, 7 & 8 presynaptic, usually inhibit glutamate (and other transmitters) release by decreasing Ca influx
  3. Different receptors are location, synapse and tissue specific
28
Q

Describe how presynaptic glutamate receptors control release of glutamate

A
  1. Presynaptic- NMDA, mGluR and KAR
  2. Controls glutamate transmitter release
  3. mGluR- inhibits transmitter release
  4. NMDA- promotes transmitter release
  5. presynaptic NMDAr increase glutamate release by increasing Ca influx
  6. presynaptic mGluR decrease glutamate release by decreasing Ca influx

A PA20023 (19 decks)

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