16. Glutamate, GABA neurotransmission Flashcards by Aurora H

Neurotransmitters can not cross the BBB
=> Which amino acid can enter?

Essential AAs
Arginine
Tyrosine

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Glutamatergic synapse
-> Characteristics of Glutamin transporters

System N/A transporters (Sodium-coupled neutral amino acid)

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Describe Glutamate transporters

EAAT: 1 glutamate enter + 3 sodium enter➔
1 glutamate / 1 ATP

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3 Glutamatergic ionotrop receptors

NMDA
AMPA
Kainate

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List Glutamatergic metabotrop receptors:

mGluR -

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Ionotropic glutamate receptors agonists and antagonists
-> What are some Specific agonists:?

NMDA – N-methyl-D-aspartate

AMPA – alpha-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid

Kainate: 2-Carboxy-3-carboxymethyl-4- isopropenylpyrrolidine

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Ionotropic glutamate receptors agonists and antagonists
-> What is 2 important antagonists?

1/ Phencyclidine
2/ Ketamine

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Pharmacologic binding sites of the NMDA receptor
-> Identify

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The synaptic AMPA & NMDA receptors are coincidence receptors
-> How do they work?

AMPA & NMDA receptors simultaneously present – ion channels

AMPA activation (Na+ permeability) → depolarization → Mg2+ detaches → Mg2+ inhibition on NMDA receptor ↓ → NMDA activation → [Ca2+]i rises

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Dual-component Excitatory Postsynaptic Potential (EPSP)
-> What happen after activation of AMPA?

Activation of AMPA
➔ depolarisation
➔ Mg2+ inhibition of NMDA decreases
➔Activation of NMDA receptors

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Characteristics of Metabotropic glutamate receptors

-mGluR- pre- and postsynaptic localization
-Various intracellular signalling pathways: Gq, Gi

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Metabotropic glutamate receptors have the regulation of ___

Ion channels
1/ L-N type Ca2+ channels ↓
1/ K+-channels ↓

Receptors
(NMDA, AMPA, DA, GABA, NA) ↑or↓

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How does Ca2+ homeostasis in neurons work?

Activation of Ca2+ -dependent enzymes

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Ca2+ homeostasis in neurons
-> List 5 Ca2+ -dependent enzymes

1/ PKC
2/ NO synthase
3/ Ca2+-calmodulin dept. prot. kinases
4/ Calcineurin (phosphatases)
5/ Phospholipase A2

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LTP (long-term potentiation: a model of learning
-> Identify

1/ NMDA receptor
2/ AMPA receptor

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Mechanisms of long-term potentiation
-> What happen during normal transmission?

Only AMPA receptors activated

Mechanisms of long-term potentiation
-> What happen after conditioning train?

1/ AMPA, NMDA, mGlu1 receptors activated
2/ Increased [Ca2+]I
3/ Activation of CaMKII, PKC, and NOS

What is the role of CaMKII

calcium-calmodulin–dependent protein kinase II. (drugs that block CaMKII prevent LTP)

Events that lead to cell death, including apoptosis and necrosis, after ischemia

The role of GABA – γ-aminobutirate

major inhibitory neurotransmitter in the central nervous system (glycin: brainstem)

2 Toxins that destroy synaptic SNARE proteins

1/ Tetanus toxin
2/ Botulinum toxin

2 Toxins that destroy synaptic SNARE proteins

1/ Tetanus toxin
2/ Botulinum toxin

Toxins that destroy synaptic SNARE proteins
-> The role of Tetanus toxin

1/ acts selectively to prevent glycine release
from inhibitory interneurons in the spinal cord, causing excessive reflex hyperexcitability
and violent muscle spasms (lockjaw)

Toxins that destroy synaptic SNARE proteins
-> The role of Botulinum toxin

prevents acetylcholine release
- prevents contraction
- muscle relaxant
- toxin-induced paralysis

What is GABA A channel receptor? (γ-Aminobutyric acid, or GABA)

a heteropentamer that not only has a pore for Cl− but also separate binding sites for GABA and several classes of channel modulators

Mechanism of GABA A channel receptor

Chloride equilibrium potential is more negative than the resting membrane potential → chloride influx → hyperpolarization

All drugs which increase inhibitory neurotransmission through positive allosteric modulation of the GABAergic neurotransmission -> they can cause.... (in case of increasing dose)

* anxiolytic action (unfortunately not fully distinguisable from sedation – lowest dose) * hypnotic action (moderate dose) * general anesthesia (still higher dose) * coma and death (toxic dose) * There is an additive synergism among the GABAergic or other sedatives and ethanol.

Synthesis of GABA -> Identify

γ-Aminobutyric acid, or GABA

The role of GAD

– cytosolic, expressed only in GABAergic neurons (some in non-neuronal tissues?) - (two isoforms with slightly different molecular weight (GAD65 and GAD67)) - inhibition → convulsion

How does Degradation of GABA occur?

What is GABA-T? How does it work?

GABA-T – mitochondrial GABA analog – (Vibagatrin, γ-vinyl GABA) → irreversible covalent binding to GABA-T → elevation of synaptic GABA → antiepileptic effect

GABA shunt -> Identify

1/ gamma-Amino butyrate 2/ SSADH - Succinic semialdehyde dehydrogenase

Neuron – glia interaction in the metabolism of GABA and glutamate -> Where are GABA transporters (GATs)

neurons astrocytes (~ 20 % of released GABA is taken up by astrocytes)

Characteristics of GABA transporters (GATs) – neurons astrocytes

- Na+-dependent - functions against a GABA concentration gradient - bidirectional - (GAT1 – primarily on presynaptic GABAergic terminals, GAT3 on astrocytic processes, GAT2 extrasynaptic region)

what are GAT inhibitors?

anticonvulsants

What are the 2 types of GABA receptors

1/ GABAA receptor – ligand-gated chloride ion channels 2/ GABA B receptor – dimeric G-protein coupled receptor

The role of GABAA receptor – ligand-gated chloride ion channels

1/ produce rapid phasic (synaptic) and tonic (extrasynaptic) inhibitory currents 2/ targets of benzodiazepines (anxiolytics) anaesthetics, ethanol

What are characteristics of GABA B receptor – dimeric G-protein coupled receptor?

coupled to a variety of effectors (some receptors activate certain K+ channels producing slow inhibitory synaptic currents, others decrease Ca2+ conductance and /or inhibit cAMP production) Mediate pre and postsynaptic inhibition)