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neuropharm midterm 2 > Glutamate and GABA > Flashcards

Glutamate and GABA Flashcards

1
Q

GABA

A

GABA is the chief inhibitory neurotransmitter in the brain.
- Reduces excitability of cells;

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2
Q

Glutamate

A

Glutamate is the main excitatory neurotransmitter in the
brain.
- Is present in more synapses than any other neurotransmitter
(that we know of)

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3
Q

Glutamate is synthesized from the

A

the conditionally
essential amino acid glutamine.

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4
Q

Glutamine can be manufactured in

A

the body

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5
Q

Glutamine is involved in … detoxification

A

ammonia

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6
Q

Neurons can transform glutamine into glutamate
using an enzyme called

A

glutaminase

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7
Q

Once synthesized, glutamate is packaged into…. by …

A

Once synthesized, glutamate is packaged into
vesicles by three different proteins

VGLUT1, VGLUT2 & VGLUT3;
- Together, these proteins are called vesicular
glutamate transporters (VGLUT)

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8
Q

In order to identify glutamatergic neurons, we look
for

A

VGLUT

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9
Q

Glutamate, like other neurotransmitters, is released
following a rise in

A

intracellular Ca2+ levels

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10
Q

Following release, glutamate is rapidly taken back into the
presynaptic cell by a family of five different transporter
proteins:

A

excitatory amino acid transporters (EAATs)
- EAAT1  5, each with different cellular localizations;
- Astrocytes (EAAT1,2) take up more glutamate than do neurons;
- Major neuronal glutamate transporter is EAAT3;
- EAAT4 are common on Purkinje cells

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11
Q

After astrocytes have taken up glutamate, they convert a major portion of it back to glutamine via

A

glutamine synthetase

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12
Q

Once released into the synaptic cleft,
glutamate has threecionotropic post-synaptic
receptors to bind to:

A
  1. AMPA receptors  inward, fast current;
  2. NMDA receptors  inward, slow current;
  3. Kainate receptors  inward, fast current.
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13
Q

All 3 ionotropic post-synaptic
receptors allow Na+ entry into the cell, and therefore cause

A

depolarization and excitatory
postsynaptic responses

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14
Q

Arguably the most important
physiological function mediated
by glutamate is

A

synaptic plasticity
- Changes in the strength of
synaptic connections between
2+ neurons;
- Learning & memory;
- Long-term potentiation (LTP);
- Implicated in chronic drug use,
addiction, withdrawal, etc.;

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15
Q

Kainate receptors, likewise, are ionotropic receptors
permeable to

A

Na+ and can depolarize a cell.

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16
Q

Both AMPA and Kainate (and NMDA) receptors are
comprised of four subunits that come together to form a

A

receptor channel

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17
Q

(NMDA) receptors
are distinct from AMPA and Kainate receptor
subtypes in several ways

A
  1. Permeable to Ca2+ and Na+, and can therefore
    trigger Ca2+ dependent 2nd messenger systems;
  2. Opening of NMDA requires a co-agonist in
    addition to glutamate (glycine or D-serine);
  3. NMDA receptors possess a binding site for Mg2+
    within the ion pore;
    - Mg2+ block must be expelled by change in polarity before
    NMDA receptor pore can open.
  4. NMDA receptors also possess binding sites for
    PCP, ketamine, memantine, MK-801, alcohol,
    benzodiazepines, barbiturates, etc
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18
Q

NMDA is a coincidence detector
 only activates when

A

two
events occur close together in
time.
1. Glutamate released onto NMDA;
2. Cell membrane is depolarized

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19
Q

n addition to the 3 ionotropic receptors, glutamate
also has ….. metabotropic receptors

A

8

20
Q

Long-term potentiation is mediated by activity of the

A

NMDA receptors

21
Q

Long-term potentiation (LTP) is defined as

A
  • A persistent (>1 hour) increase in synaptic strength produced by a burst of
    activity in the presynaptic neuron;
  • Initiated by a burst of firing activity (100 stimuli in ~1s) called tetanus;
  • Synaptic enhancements produced by the tetanus is measured in EPSPs on
    the post-synaptic cell;
22
Q

There are many varieties of LTP

A
  • Time period of potentiation (E- vs. L-LTP);
  • Pre-synaptic vs. post-synaptic;
  • Structural vs. biochemical modifications (or both);
  • Underlying cellular mechanism.
23
Q

LTP occurs in many brain regions but was
first discovered in the

A

hippocampus

24
Q

The hippocampus is divided into three
principle pathways:

A
  • Perforant path: entorhinal cortex  granule
    cells;
  • Mossy fibers: granule cells  pyramidal cells
    in CA3;
  • Schaffer collateral: CA3  CA1 (main
    pathway in LTP
25
Q

Glutamate binds to both …….receptor

A

AMPA & NMDA

26
Q

Once Ca2+ enters the cell via NMDA
receptors, it alters the postsynaptic
neuron by:

A
  1. Increasing responsiveness of AMPA
    receptors to glutamate (how?);
  2. Increase the number of AMPA receptors
    expressed on the post-synaptic
    membrane;
  3. Triggers the release of retrograde
    messengers that cause more glutamate
    to be released from presynaptic neuron.
27
Q

Blocking NMDA receptors, particularly in the hippocampus, can interrupt the
formation of

A

spatial memories

28
Q

Excitotoxicity can occur with overexposure to glutamate
caused by a prolonged depolarization of the

A

postsynaptic neuron

29
Q

When both NMDA and non-NMDA receptors are
subjected to prolonged stimulation by glutamate,
a large % of cells die via 1 of 2 mechanisms:

A

necrosis and apoptosis

30
Q

necrosis and apoptosis

A
  1. Necrosis: characterized by rapid lysis of the cell due
    to osmotic swelling;
  2. Apoptosis: delayed cascade of biochemical events
    that leads to DNA breakup and ultimately cell death
31
Q

GABA is synthesized in

A

GABAergic
neurons,

32
Q

GABA is made from glutamate, a reaction
that is catalyzed by the enzyme

A

glutamic
acid decarboxylase (GAD).

33
Q

The vitamin B6 derivative pyridoxal
phosphate is a cofactor in the synthesis of

A

GABA

34
Q

Labeling of GAD in presynaptic nerve terminals shows us that GABA synthesis is localized with

A

mitochondria

35
Q

Following synthesis in the nerve terminals,
GABA is stored in vesicles via

A

vesicular GABA
transporters (VGAT)

36
Q

VGATs are also capable of transporting glycine
into vesicles and are therefore also known as

A

vesicular inhibitory amino acid
transporters (VIAAT)

37
Q

GABA is removed from the synaptic cleft
by three different transporters:

A

GAT-
1, GAT-2 & GAT-3

38
Q

Once recycled, GABA is then metabolized
back to glutamate and succinate by

A

GABA aminotransferase (GABA-T

39
Q

The best characterized binding site is the

A

benzodiazepine
site (BzR

40
Q

Prototypical GABAA receptors are:

A

Selectively activated by muscimol:
- Found in Fly Agaric mushrooms (and others);
- Eaten for its stimulatory and hallucinogenic effects.
Antagonized competitively by bicuculline:
- Blocks binding of GABA to GABAA;
- Potent convulsant.
Antagonized non-competitively by picrotoxin.
- Acts as a stimulant and convulsant;
- Can cause respiratory paralysis.

41
Q

Because the GABAA receptor has
multiple binding sites, the activity at
the receptor can be exacerbated by

A

multiple ligands binding

42
Q

The action of alcohol,
benzodiazepines (BDZs) and
barbiturates potentiate the effects
of

A

GABA on the GABAA receptor

43
Q

Barbiturates:

A
  • E.g. Pentobarbital;
  • Increase the mean duration of opening time;
  • Increase the mean number of openings per burs
44
Q

Benzodiazepines

A
  • E.g. Valium
  • Increase the open frequency of GABAA (BDZ agonis
45
Q

Picrotoxin

A
  • Does not directly interact with binding site for
    barbiturates, but produces the opposite effects on the
    receptor;
  • Reduces the mean number of openings per burst;
  • Shortens the mean opening time;
46
Q

Barbiturates are a unique ligand for the
GABAA receptor, as they exhibit three
modes of action, depending on the
concentration

A
  1. At low concentrations, barbiturates act
    allosterically on the GABA-gated Cl-
    influx  co-agonist;
  2. At higher concentrations, barbiturates
    open GABAA receptor channel directly,
    independent of the presence of GABA 
    agonist;
  3. At very high concentrations, barbiturates
    block the Cl- current  antagonis

neuropharm midterm 2 (5 decks)

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