21- Glutamate Flashcards

1
Q

define a neurotransmitter

A

a chemical messenger that transmits signals from a neuron to a target cell across a synapse

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2
Q

what are the criteria for neurotransmitters? (3)

A
  • molecule synthesised and stored in pre-s neurone
  • molecule released by pre-s axon terminal when stimulated
  • molecule produces a response in the post-s cell
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3
Q

how are neurone classified?

A

based on differential gene expression of proteins involved in NT synthesis, storage and release

differences in neuronal structure

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4
Q

define glutamate

A

the major excitatory NT in the CNS

nearly half of all CNS excitatory neurons are glutamatergic

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5
Q

describe the synthesis of glutamate

A

glutamine converted to glutamate by glutaminase, a phosphate activated enzyme

glutamate is synthesised in nerve terminals

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6
Q

describe glutamate transport into (pre)synaptic vesicles

A

glutamate transported into synaptic vesicles by VGLUT transporter = different VGLUT subtypes involved

transported via a counter-transport process = vesicle environment is acidic maintained by an ATP-driven proton pump which pumps H+ down a conc. grad into the vesicle

drives glutamate entry into vesicle via VGLUT transporter

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7
Q

describe glutamate reuptake from the synaptic cleft

A

EAATs transporters on glial cells and neurons - Na+ ion dependent co-transporters

transporters take glutamate from the synaptic cleft into pre-s neurons/ glial cells

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8
Q

describe glutamate degradation

A

glutamate converted to glutamine via glutamine synthase in glial cell

glutamine exported out of glial cells by SN1

glutamine transported into neurons by SAT2

creates a glutamine-glutamate cycle for synthesis and degradation

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9
Q

what does EAATs stand for?

A

excitatory amino acid transporters

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10
Q

what are the two types of glutamate receptors and their subtypes

A

ionotrophic/LGIC:
- AMPA receptors
- NMDA receptors
- kainate receptors

metabotrophic/GCPR:
- group 1 = mGlu 1,5
- group 2 = mGlu 2,3
- group 3 = mGlu 4, 6, 7, 8

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11
Q

describe the ionic movements through each of the ionotropic glutamate receptors

A

all allow Na+ influx and K+ efflux

NMDA receptors also allow Ca2+ influx = important for long term potentiation

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12
Q

describe the AMPA receptor

A

post-synaptic receptor, consists of four subunits = GluA1-4 with alternate splice variants

receptor composed of four subunits, hetero-tetrameric:
- two GluA2 subunits
- two of GluA1/3/4 in any combination

presence of GluA2 subunits makes the receptor impermeable to Ca2+ activity - Ca2+ has many excitatory intracellular effects, meaning GluA2 serves a protective role against potential excito-toxicity

receptor has 4 orthosteric binding sites, only two need to be occupied for IC opening

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13
Q

significance of GluA2 subunit?

A

makes the receptor impermeable to Ca2+ activity

protects against potential excito-toxicity

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14
Q

describe the NMDA receptor

A

three subunit types with alternate splice variants - GluN1-3

hetero-tetrameric receptor composed of four subunits
- two GluN1
- two GluN2 or two N3 = N3 is inhibitory to NMDA receptor function

has ligand-gated and voltage-gated properties
- ligand-gated = glutamate binds to N2, glycine/D-serine binds to N1. all four binding sites must be occupied for the IC to open

  • voltage gated = Mg2+ ion blocks the C at resting membrane potential. with depolarisation, the Mg2+ moves, allowing ion passage through the IC
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15
Q

describe the kainate receptor

A

5 subunit types with alternate splice variants = GluK1-5

GluK1-3 can form homomers or heteromers
GluK4 and 5 can only form heteromers with GluK1-5

less is known about this receptor, don’t know number of glutamates that need to bind for IC to open. distributed less in the brain.

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16
Q

what is a homomer?

A

structure consisting of identical parts; multiple units of the same protein

17
Q

describe metabotropic glutamate receptors

A

8 receptor subtypes (mGlu1-8) organised into three groups based on distinct properties:
group 1 = mGlu 1,5
group 2 = mGlu 2,3
group 3 = mGlu 4, 6, 7, 8

form dimers = homomers and heteromers with one another and other receptor types (e.g. 5-HT2A)

group 1 receptors are post-synaptic, involved in synaptic plasticity and LTP and Gq coupled
- activates phospholipase C
- IP3 as second messenger, along with DAG
- release Ca2+ from stores, increase intrac. Ca2+

group 2 and 3 are pre-synaptic, involved in inhibiting neurotransmitter release as autoreceptors and are Gi/o coupled
- inhibit adenylyl cyclase
- inhibit cAMP production
- inhibit NT release

18
Q

differences between group 1 glutamate metabotropic receptors and group 2&3

A

group 1 receptors:
- post-synaptic
- involved in synaptic plasticity and LTP
- Gq coupled

group 2 & 3 receptors:
- pre-synaptic
- involved in inhibiting neurotransmitter release, act as autoreceptors
- Gi/o coupled

19
Q

what is excito-toxicity? how can it occur with glutamate when there is damage to VGLUT transporters?

A

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

  • damage to VGLUT transporters = glutamate accumulates in pre-s cytosol instead of being transported into vesicles
  • glutamate build-up means EAATs transporters won’t be reuptaking glutamate from the synaptic cleft = will instead pump glutamate out of the neurone into the synapse
  • overactivation of post-s AMPA and NMDA receptors
  • uncontrolled Ca2+ and Na+ influx into post-s neurone

excess Ca2+ can case mitochondrial damage, apoptosis and oxidative stress

20
Q

what is Alzheimer’s?

A

neurodegenerative disorder characterised by neuronal cell death in the hippocampus – results in neuronal cell death in the cerebral cortex

21
Q

how is Alzheimer’s linked to glutamate? considering this relationship, describe memantine as a treatment for Alzheimer’s?

A

glutamate neurotoxicity causing NMDA receptor overactivation = leads to neuronal cell death from excess Ca2+

memantine is a low affinity NMDA receptor antagonist - blocks excessively open NMDA receptor channels, reduces glutamate neurotoxicity and neuronal cell death

22
Q

describe synaptic plasticity

A

ability for neurons to modify the strength of their synaptic transmissions

23
Q

describe long-term potentiation

A

the persistent strengthening of a synapse based upon repeated patterns of activity

24
Q

describe the initial phase of LTP

A

involves AMPA and NMDA post-s receptors

  • two glutamate molecules bind to and activate AMPA receptors
  • opening of ion channel causes Na+ influx = post-s membrane depolarisation
  • depolarisation opens up NMDA receptor ion channel = voltage-gated property, Mg2+ ion block is removed
  • allows Ca2+ influx
  • activates post-s protein kinases = calmodulin kinase and protein kinase C
  • trigger a series of reactions that leads to the insertion of AMDA receptors on the post-synaptic membrane

increase AMPA receptors, increase sensitivity to glutamate and ion channel conductance

later LTP phases include changes in gene expression