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PSYCH 478 > Topic 10: Glutamate > Flashcards

Topic 10: Glutamate Flashcards

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1
Q

What are amino acid neurotransmitters?

A

non-essential amino acids: not required in diet, synthesized in most cells of the body

two functional groups: excitatory and inhibitory amino acid NT

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2
Q

What are excitatory amino acid NT?

A

glutamate, aspartate, cysteate, homocysteate

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3
Q

What are inhibitory amino acid NT?

A

gamma-aminobutyric acid (GABA), glycine, taurine, alanine

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4
Q

What is aspartate?

A

released in a calcium-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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5
Q

What is 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 cell, concentrated in presynaptic compartments

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6
Q

How is glutamate synthesized?

A

glutamate synthesis from glutamine

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

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7
Q

What are glutamate transporters?

A

glutamate is abundant throughout the cell

neurotransmitter glutamate is packaged into vesicles to maintain a seperate “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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8
Q

Where are VGLUT1 and 2 expressed?

A

VGLUT1 and 2 are expressed on distinct glutamatergic populations in the CNS

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9
Q

Where is VGLUT3 expressed?

A

VGLUT3 is expressed in various neurons including GABAergic, cholinergic, and monoaminergic neurons suggesting possible modulatory functions

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10
Q

How is glutamate metabolized?

A

glutamate is metabolized to glutamine

glutamine synthetase is the enzyme responsible for conversion of glutamate to glutamine

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11
Q

How are EAATs responsible for reuptake of glutamate?

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)

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12
Q

What are the five families of EAATs?

A

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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13
Q

What are glia in the CNS?

A

neurons comprise only 50% of the cells in the CNS

the remaining 50% of cells are termed glia

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14
Q

What are the different types of glial cells in the CNS?

A

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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15
Q

What are the functions of astrocytes?

A

define the blood brain barrier: regulate intake of nutrients and oxygen

regulate blood flow in the brain

form extensive signaling networks: coupled with electrical synapses, gap junctions

regulate synaptic functions and contribute to plasticity

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16
Q

How are astrocytes involved in 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 moues cortex increases cognitive measures

17
Q

What are 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 especially 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)

18
Q

How are glutamate synapses an example of tripartite synapses?

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

19
Q

How does MSG cause glutamatergic injury?

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

20
Q

What are the systems that contain glutamatergic neurons?

A

pyramidal neurons of the cerebral cortex: projections to striatum, thalamus, limbic, brainstem

corticospinal tracts: voluntary motor control

parallel fibers of the cerebellum: excitatory inputs to Purkinje cells

hippocampus

21
Q

What are glutamate receptors?

A

glutamate is responsible for fast excitatory synaptic transmission: the most important receptors are ionotropic

synaptic transmission elicits excitatory postsynaptic potentials (EPSP)

huge number of genes involved in GluR expression (16 for ionotropic, 8 for metabotropic)

22
Q

What are ionotropic glutamate receptors?

A

AMPA receptors

kainate receptors

NMDA receptors

23
Q

What are metabotropic glutamate receptors?

A

group 1: mGluR1, mGluR5, Gq –> PLC Ca2+

group 2: mGluR2, mGluR3, Gi –> decreased cAMP

group 3: mGluR4, mGluR6, mGluR7, mGluR8, Gi –> decreased cAMP

24
Q

What are AMPA receptors?

A

named for the specific agonist: synthetic amino acid

non-selective cation channel (passes both Na+ and K+)

four types of subunits (GluR1-4) from heterotetramers (dimers of dimers)

rapid kinetics: onset, offset, desensitization occur within milliseconds, single channel conductance on picosecond timescale (10-12 s)

experimental antagonists: NBQX, CNQX, DNQX

specific mutations in AMPAR (GRIN2A gene) associated with 58% decrease in Parkinson’s risk if also a heavy coffee drinker

25
Q

What are kainate receptors?

A

functionally similar to AMPA receptors

5 subunits (termed GluR5-7, KA1-2, also known as GluK1-5)

selective agonist is kainate, an isolate from Digenea simplex, a red seaweed

somewhat slower than AMPAR

limited role in fast, excitatory transmission: can be expressed presynaptically at GABAergic synapses

26
Q

What is the pharmacology of AMPA and kainate receptors?

A

AMPA and kainate receptors have very similar pharmacology

difficult to distinguish experimentally

agonists at kainate and AMPA receptors cause seizures: kainic acid is used as a model of epilepsy, repeated administration causes development of spontaneous seizures

27
Q

What are the agonists of AMPA and kainate receptors?

A

kainate/kainic acid: kainate > AMPAR

AMPA: AMPAR&raquo_space; kainate

domoic acid: kainate > AMPAR, causes amnesiac shellfish poisoning in humans

28
Q

What are the antagonists of AMPA and kainate receptors?

A

NBQX: AMPAR&raquo_space; kainate

NS102: kainate&raquo_space; AMPAR

29
Q

What are NMDA receptors?

A

widely distributed: cortex, hippocampus, basal ganglia, septum, cerebellum

always co-expressed with either AMPA or kainate receptors

permeable to calcium as well as sodium and potassium

highly regulated: 6 binding sites for endogenous ligands and modulators

important in learning and memory processes by modulating synaptic strength

30
Q

What are NMDAR binding sites?

A

glutamate site: obligatory agonist binding site

glycine/D-serine site: obligatory co-agonist binding site

polyamine binding site: site of endogenous allosteric modulation (positive)

Mg2+ binding site: voltage dependent block of channel opening

Zn2+ binding site: negative allosteric modulation site

H+ binding: pH sensitive negative modulation

31
Q

What is NMDA receptor gating?

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

32
Q

What are NMDA receptor agonists?

A

endogenous: glutamate and glycine/D-serine (both obligatory), polyamines (e.g., spermine, spermidine) - allosteric modulators

exogenous: NMDA - synthetic amino acid

33
Q

What are NMDA receptor antagonists?

A

endogenous: Zn2+ (allosteric), Mg2+

exogenous: MK801 (widely used experimental antagonist, non-competitive), PCP and ketamine (dissociative anesthetics/recreational, non-competitive)

PSYCH 478 (28 decks)

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