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Psych 478 > Glutamate > Flashcards

Glutamate Flashcards

1
Q

What are non-essential amino acids?

A
  • Not required in diet
  • Synthesized in most cells of the body
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2
Q

What unites all amino acid neurotransmitters?

A

They all have two functional groups

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3
Q

What are the excitatory neurotransmitters?

A
  • Glutamate, Aspartate, Cysteate, Homocysteate
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4
Q

What are the inhibitory neurotransmitters?

A
  • γ-aminobutyric acid (GABA), Glycine, Taurine, Alanine
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5
Q

Describe aspartate

A
  • Released in a Ca2+-dependent manner
  • May not be stored in secretory vesicles
  • May be directly released from cell cytoplasm
  • Not considered a ‘classic’ neurotransmitter
  • Acts at glutamatergic receptors
  • Physiological functions unclear
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6
Q

Describe glutamate

A
  • Most widely used excitatory neurotransmitter
  • ~90% of all neurons, 80-90% of all synapses are
    glutamatergic
  • Mediates fast excitatory neurotransmission
  • Sensory, motor coordination, emotion, cognition, memory formation and retrieval
  • Proteinogenic amino acid
  • Abundant throughout the cell
  • Concentrated in presynaptic compartments
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7
Q

What is glutamate synthesized from?

A

Glutamine

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8
Q

Describe how this synthesis occurs

A

In the CNS the majority of glutamate is recycled from glutamine by the enzyme glutaminase

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9
Q

Describe glutamate transporters

A
  • Glutamate is abundant throughout the cell
  • Neurotransmitter glutamate is packaged into
    vesicles to maintain a separate ‘pool’ of NT
  • Vesicular glutamate transporter (VGLUT) can be used to identify glutamatergic neurons
  • Family of 3 transporters
  • VGLUTs are structurally and functionally similar to VMAT
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10
Q

Where are VGLUT family members expressed?

A
  • VGLUT1 and 2 are expressed on distinct glutamatergic populations in the CNS.
  • VGLUT3 is expressed in various neurons including GABAergic, cholinergic, and monoaminergic neurons suggesting possible modulatory functions.
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11
Q

What is glutamate metabolized to?

A

Glutamine

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12
Q

What is the enzyme responsible for conversion of glutamate to glutamine?

A

Glutamine synthetase

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13
Q

What is responsible for re-uptake?

A

excitatory amino acid transporters (EAATs)

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14
Q

Describe EAATs

A
  • Glutamate transporters on the cell membrane are termed excitatory amino acid transporters (EAATs)
  • Non-specific for both glutamate and aspartate
  • Family of 5 transporters (EAAT1- 5)
  • EAAT1 and 2 are expressed on astrocytes
  • EAAT3 and 4 are expressed on neurons
  • EAAT5 is expressed in the retina
  • EAAT expression compartmentalizes glutamate recycling
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15
Q

Describe glia in the CNS

A
  • Neurons comprise only 50% of the cells in the CNS.
  • The remaining 50% of cells are termed glia (latin for glue).
  • Astrocytes – define the brain side of the BBB
  • Oligodendrocytes – myelinate axons in white
    matter
  • Ependymal cells – generate and regulate CSF
  • Microglia – immune surveillance and development
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16
Q

What are the functions of astrocytes?

A
  • Define the blood brain barrier
  • Regulate intake of nutrients and O2
  • Regulate blood flow in the brain
  • Form extensive signalling networks
  • Coupled with electrical synapses – Gap junctions
  • Regulate synaptic functions and contribute to plasticity
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17
Q

Describe astrocytes and cognition

A
  • Human astrocytes show dramatic difference from rodent
  • Some consider the ratio of glia to neurons a species marker of intelligence
  • Proposed to contribute to cognitive processes
  • Grafting human astrocytes into mouse cortex increases cognitive measures
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18
Q

Describe the functional effects of EAATs

A
  • High levels of extracellular glutamate are toxic to neurons
  • Genetic knockdown of EAAT 1 and 2 (astrocytic) result in widespread increases in glutamate levels esp. in the striatum
  • Knockdown of activity of EAAT3 (neuronal type) has much more limited effects
  • Astrocyte pathway of glutamate recycling is the dominant pathway
  • EAAT2 abnormalities are observed in amyotrophic lateral sclerosis (ALS)
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19
Q

Describe the tripartite synapse

A
  • Glutamatergic synapses are wrapped by
    astrocyte processes expressing EAAT1/2.
  • Glutamate uptake into astrocytes is rapid, high efficiency, and prevents spillover of glutamate into adjacent synapses.
  • Astrocytes are the principal site of glutamate breakdown.
  • Glutamine is exported from astrocytes and taken up into neurons to be converted back to glutamate.
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20
Q

Describe MSG

A
  • MSG can be used experimentally to induce glutamatergic lesions
  • MSG is proposed as one of the five basic tastes (referred to as umami)
  • Acts on glutamate receptors on the tongue
  • MSG syndrome is a widely reported reaction to MSG

Sodium glutamate (aka monosodium glutamate, MSG)

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21
Q

Describe pyramidal neurons

A

Projections to striatum, thalamus,
limbic, brainstem

22
Q

Describe corticospinal tracts

A

Voluntary motor control

23
Q

Describe Parallel fibers of cerebellum

A

Excitatory inputs to Purkinje cells

24
Q

What is another glutamatergic system?

A

The hippocampus

25
Q

What is the agonist of AMPA receptors?

A

The synthetic AA AMPA

26
Q

What is the channel type of AMPA receptors?

A

Non-selective cation channel (accepts both Na and K)

27
Q

What are the AMPA receptor subunits?

A

GluR1-4

28
Q

Describe the composition of AMPA receptors

A

Heterotetramers aka dimers of dimers

29
Q

Describe AMPA receptor kinetics

A
  • Rapid kinetics
  • Onset, offset, desensitization occur within
    milliseconds
  • Single channel conductance on picosecond
    timescale (10-12 s)
30
Q

Describe AMPA antagonists

A

Experimental antagonists: NBQX, CNQX, DNQX

31
Q

What mutations impact AMPAR?

A
  • Specific mutations in AMPAR (GRIN2A gene)
    associated with 58% decrease in Parkinson’s
    risk if also a heavy coffee drinker
32
Q

What is the agonist of kainate receptors?

A

Kainate

33
Q

What are kainite receptor subunits?

A

GluK1-5

34
Q

Describe kainate receptor kinetics

A

Slower than AMPAR

35
Q

What is the antagonist of kainate receptors?

A

NS102

36
Q

What is the function of kainate receptors

A
  • Limited role in fast, excitatory
    transmission
  • Can be expressed presynaptically at GABAergic synapses

Agonists cause seizures (same for AMPA)

37
Q

What are the endogenous agonists of NMDA receptors?

A

Glutamate & glycine

38
Q

What are the exogenous agonists of NMDA receptors?

A

NMDA → synthetic AA

39
Q

What type of channel do NMDA receptors have?

A

Non-selective cation channel (accepts both Na, K & Ca2+)

40
Q

Describe the glutamate binding site

A

obligatory agonist binding site

41
Q

Describe the glycine binding site

A

obligatory co-agonist binding site

42
Q

Describe polyamine binding site

A

Site of endogenous allosteric
modulation (positive)

43
Q

Describe the magnesium binding site

A

voltage dependent block of channel
opening

44
Q

Describe the zinc binding site

A

negative allosteric modulation site

45
Q

Describe the hydrogen binding site

A

pH sensitive negative modulation

46
Q

Describe what makes NMDA unique

A

Co-expressed with either AMPAR or kainate

47
Q

Describe NMDAR kinetics

A

Under normal resting state
conditions Mg2+ occupies the
channel pore.

Agonist binding alone is insufficient
to allow ion flux.

The pore is ‘unblocked’ when a
depolarization is previously present
– displacing Mg2+ in an voltage-
dependent manner.

NMDA receptors are only active
after an initial depolarization
(through AMPA receptors).

NMDA is described as a
coincidence detector – opening
only under conditions of strong or
repeated stimulation.

48
Q

Describe endogenous NMDAR antagonists

A

Zinc (allosteric) and Mg

49
Q

Describe exogenous NMDAR antagonists

A

noncomp MK801, noncomp PCP and Ketamine

50
Q

What is the function of NMDA receptors?

A

Important in learning and
memory processes by
modulating synaptic strength

Psych 478 (28 decks)

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