Glutamate Flashcards by Cambell Meier

Amino acid neurotransmitters

Not required in diet
Synthesized in most cells of the body

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Two functional groups of Amino acid neurotransmitters

Excitatory amino acid NT
Inhibitory amino acid NT

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Excitatory amino acid NT (4)

Glutamate, Aspartate, Cysteate, Homocysteate

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Inhibitory amino acid NT (4)

γ-aminobutyric acid (GABA), Glycine, Taurine,
Alanine

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Excitatory amino acid neurotransmitters Aspartate Released in a

Ca2+
-dependent manner

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Aspartate May not be stored in

secretory vesicles

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Aspartate May be directly released from

cell cytoplasm Not considered a ‘classic’ neurotransmitter

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Aspartate Acts at

glutamatergic receptors

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Aspartate Physiological functions

unclear

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Excitatory amino acid neurotransmitters Glutamate

Most widely used excitatory neurotransmitter

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Glutamate____of all neurons, ______of all synapses are
glutamatergic

90% of all neurons, 80-90% of all synapses are
glutamatergic

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Glutamate mediates fast

excitatory neurotransmission

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Glutamate Mediates fast excitatory neurotransmission

Sensory, motor coordination, emotion, cognition,
memory formation and retrieval

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Glutamate Proteinogenic amino acid

Abundant throughout the cell
Concentrated in presynaptic compartments

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Glutamate
synthesis from
glutamine

Glutamine —glutaminase —> glutamate

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In the CNS the majority
of glutamate is
recycled from

glutamine by the
enzyme glutaminase

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Glutamate
transporters

Vesicular glutamate transporter (VGLUT) can be
used to identify glutamatergic neurons

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VGLUTs are structurally and functionally similar to

VMAT

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VGLUT1 and 2 are expressed
on

distinct glutamatergic
populations in the CNS.

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VGLUT3 is expressed in (3 neurons
)

various neurons including
GABAergic, cholinergic, and
monoaminergic neurons
suggesting possible
modulatory functions.

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VGLUT2 locations

Deep cerebellar nuclei, inferior colliculus, thalamus

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VGLUT 1 locations

cerebellar cortex, hippocampus, cortex

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Glutamate is
metabolized to

glutamine

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Glutamine
synthetase is the
enzyme responsible
for

conversion of
glutamate to
glutamine

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Glutamate transporters on the cell membrane are termed

excitatory amino acid transporters (EAATs)

Glutamate transporters on the cell membrane are termed excitatory amino acid transporters (EAATs) Non-specific for both

glutamate and aspartate

how many families are in EAAT

* 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

Neurons comprise only

50% of the cells in the CNS

Glia in the CNS

Astrocytes, Oligodendrocytes Ependymal cells Microglia

Astrocytes

define the brain side of the BBB

* Oligodendrocytes

myelinate axons in white matte

Ependymal cells

generate and regulate CSF

Microglia

Immune surveillance and development

Astrocyte functions * Define the

blood brain barrier -Regulate intake of nutrients and O2

Astrocyte functions -Regulate

blood flow in the brain

Astrocyte functions Form extensive

signalling networks -Coupled with electrical synapses – Gap junctions

Astrocyte functions Regulate synaptic

functions and contribute to plasticity

Astrocytes and cognition

* Proposed to contribute to cognitive processes - more astrocytes increased cognition

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)

Glutamatergic synapses are wrapped by

astrocyte processes expressing EAAT1/2.

Glutamate uptake into astrocytes is

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

* MSG can be used experimentally to

induce glutamatergic lesions

MSG is proposed as one of the five basic

tastes (referred to as umami)

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

Glutamatergic neurons and systems - Pyramidal neurons of the cerebral cortex (4)

Projections to striatum, thalamus, limbic, brainstem

Glutamatergic neurons and systems Corticospinal tracts

Voluntary motor control

Glutamatergic neurons and systems Parallel fibers of the cerebellum

Excitatory inputs to Purkinje cells

Glutamatergic neurons and systems area

Hippocampus

Glutamate receptors

The most important receptors are ionotropic

Synaptic transmission elicits

excitatory postsynaptic potentials (EPSP)

Ionotropic receptors (3)

AMPA receptors Kainate receptors NMDA receptors

Metabotropic receptors Group I

mGluR1, mGluR5 Gq → PLC, Ca2+

Metabotropic receptors Group II

mGluR2, mGluR3 Gi → ↓ cAMP

Metabotropic receptors Group III

mGluR4, mGluR6, mGluR7, mGluR8 Gi → ↓ cAMP

AMPA Receptors Four types of subunits and form

(GluR1-4) form heterotetramers (dimers of dimers)

AMPA Receptors Rapid kinetics Onset, offset, desensitization

occur within milliseconds

AMPA Receptors Rapid kinetics Single channel conductance on

n picosecond timescale (10 -12 s)

AMPA Receptors * Experimental antagonists (3)

NBQX, CNQX, DNQX

* Specific mutations in AMPAR (GRIN2A gene) associated with

58% decrease in Parkinson’s risk if also a heavy coffee drinker

Kainate receptors Functionally similar to

AMPA receptors

Kainate receptors 5 subunits (termed

GluK1 -5

Kainate receptors Selective agonist is

kainat

Kainate receptors Somewhat slower than

AMPAR

Kainate receptors Limited role in

fast, excitatory transmission

Kainate receptors Limited role in fast, excitatory transmission

Can be expressed presynaptically at GABAergic synapses

AMPA and kainate receptors have very

similar pharmacology

Agonists at kainate and AMPA receptors cause

seizures

* Kainic acid is used as a model of

epilepsy

Kainic acid is used as a model of epilepsy Repeated administration causes

development of spontaneous seizures

AMPA and Kainate pharmacology Agonists (3)

Kainate/Kainic acid AMPA Domoic acid

Kainate/Kainic acid

Kainate > AMPAR

AMPA

AMPAR >> Kainate

Domoic acid

Kainate > AMPAR

Domoic acid causes

Causes amnesiac shellfish poisoning in humans

AMPA and Kainate pharmacology Antagonists: (2)

NBQX NS102

NBQX

AMPAR >> kainate

NS102

Kainate >> AMPAR

NMDA Receptors Widely distributed (5)

Cortex, hippocampus, basal ganglia, septum, cerebellum

NMDA Receptors Always co-expressed with

either AMPA or kainate receptors

NMDA Receptors Permeable to

Ca2+ as well as Na+ and K+

NMDA Receptors Highly regulated

* 6 binding sites for endogenous ligands and modulators

NMDA Receptors * Important in

learning and memory processes by modulating synaptic strength

NMDAR binding sites (6)

Glutamate site Glycine/D-serine site Polyamine binding site Mg2+ binding site Zn2+ binding site H+ binding

NMDAR binding sites Glutamate site

obligatory agonist binding site

NMDAR binding sites Glycine/D-serine site

obligatory co-agonist binding site

NMDAR binding sites Polyamine binding site

Site of endogenous allosteric modulation (positive)

NMDAR binding sites Mg2+ binding site

voltage dependent block of channel opening

NMDAR binding sites Zn2+ binding site

negative allosteric modulation site

NMDAR binding sites H+ binding

pH sensitive negative modulation

NMDAR Gating resting state

resting state - Mg2+ occupies the channel pore

NMDAR Gating Agonist binding alone is

Is insufficient to allow ion flux.

NMDAR Gating The pore is ‘unblocked’ when a

depolarization is previously present – displacing Mg2+ in n voltage-dependent manner

NMDAR Gating 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.

NMDAR Pharmacology Agonists:

Endogenous exogenous

Endogenous NMDAR * Agonists

Glutamate and glycine / D-serine (both obligatory) Polyamines (e.g. spermine, spermidine) – allosteric modulators

Exogenous NMDAR agonist

NMDA (N-methyl-D-aspartate) – synthetic amino acid

NMDAR Pharmacology Antagonists Endogenous:

Zn2+ (allosteric), Mg2+

NMDAR Pharmacology Antagonists Exogenous

MK801 – widely used experimental antagonist – non-competitive PCP and ketamine – dissociative anesthetics / recreational – non-competitive