16. Glutamate, GABA neurotransmission Flashcards
Neurotransmitters can not cross the BBB
=> Which amino acid can enter?
Essential AAs
Arginine
Tyrosine
Glutamatergic synapse
-> Characteristics of Glutamin transporters
System N/A transporters (Sodium-coupled neutral amino acid)
Describe Glutamate transporters
EAAT: 1 glutamate enter + 3 sodium enter➔
1 glutamate / 1 ATP
3 Glutamatergic ionotrop receptors
NMDA
AMPA
Kainate
List Glutamatergic metabotrop receptors:
mGluR -
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
Ionotropic glutamate receptors agonists and antagonists
-> What is 2 important antagonists?
1/ Phencyclidine
2/ Ketamine
Pharmacologic binding sites of the NMDA receptor
-> Identify
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
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
Characteristics of Metabotropic glutamate receptors
-mGluR- pre- and postsynaptic localization
-Various intracellular signalling pathways: Gq, Gi
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↓
How does Ca2+ homeostasis in neurons work?
Activation of Ca2+ -dependent enzymes
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
LTP (long-term potentiation: a model of learning
-> Identify
1/ NMDA receptor
2/ AMPA receptor
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)
