Glutamate, GABA

neurotransmission

Beáta Törőcsik

2022. november.

Department
Szervezeti of Medical
egység megnevezése – ha
Biochemistry
hosszabb a név, két sorba tördelve
Neurotransmitters

5-HT,
5-Hydroxytryptamine
Serotonine
 The roles of glutamate

pyruvate
carboxylase
(astrocytes) * PLP
PLP

Neurotransmitters can not cross the BBB

Which amino acid can enter?
Essential AAs
Arginine
Tyrosine

*GDH:
In vivo probably irreversible (high Km towards ammonia)
GAD: glutamate decarboxylase
Glutamatergic synapse
presynaptic
neuron
glutaminase
Glutamin transporters:
System N/A transporters
(Sodium-coupled specific
neutral amino acid) astrocyte

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

Glutamatergic ionotrop receptors:

NMDA
AMPA kainate
Kainate (not-NMDA receptors)

Glutamatergic metabotrop receptors:

mGluR - postsynaptic
neuron
 Ionotropic glutamate receptors agonists and antagonists

Specific agonists:
Na+, K+ NMDA – N-methyl-D-aspartate
AMPA – alpha-amino-3-hydroxy-5-
(Ca2+ ) methyl-4-isoxazole propionic acid
Kainate: 2-Carboxy-3-carboxymethyl-4-
isopropenylpyrrolidine

Na+, K+
(Ca2+ )
phencyclidine (PCP, ‘angel dust’)

dissociative anesthetic
Na+, Ca2+ (characterised by distorted sensory perceptions
and feelings of disconnection or detachment
from the environment and self)
hallucinogen

Ketamine subanaesthetic dose:

therapy-resistent depression
 Treatment Combinations for Alzheimer’s Disease:
Current and Future Pharmacotherapy Options

Not for
biochemistry exam
Pharmacologic binding sites of the NMDA receptor

Glutamate (aspartate) and glycine - co-agonists

 The synaptic AMPA & NMDA receptors are coincidence receptors

/KAINAT

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)

Activation of AMPA ➔ depolarisation

➔Mg2+ inhibition of NMDA

➔ Activation of NMDA
receptors

Fast kinetics Slow kinetics

Comparison of ionotropic and metabotropic glutamate receptors
Not for
biochemistry
exam
 Metabotropic glutamate receptors

-G protein-coupled receptors

-mGluR- pre- and postsynaptic localization

-Various intracellular signalling pathways:

Gq, Gi

-Regulation of
Ion channels
L-N type Ca2+ channels ↓
K+-channels ↓
Receptors
(NMDA, AMPA, DA, GABA, NA)
↑or↓
Ca2+ homeostasis in neurons

Activation of
Ca2+ -dependent enzymes:

PKC
NO synthase

Ca2+-calmodulin
dept. prot. kinases

Calcineurin (phosphatases)

Phospholipase A2
 Postsynaptic density (PSD)

CA1
Not for
biochemistry exam

a=axon
b= buton, axon terminal Cerebellum
S=postsynaptic spine with PSD
*=glia

Scaffold proteins

Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
 Molecular Organization of the Postsynaptic Density Not for
biochemistry exam

Principles of Neural Science, Fifth Edition; Edited by Kandel, Eric R.; Schwartz, James H.; Jessell, Thomas M.; Siegelbaum, Steven A.; Hudspeth, A.J. Copyright © 2012 McGraw-Hill
LTP (long-term potentiation: a model of learning
Learning and memory

Mechanisms of
long-term potentiation

NO turning back
nitric oxide
facilitates
glutamate release

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
Effect of ischemic damage on rat hippocampus Not for
biochemistry exam
Hypothetical mechanism of ketamine’s rapid antidepressant effects

Not for
biochemistry exam

Ketamine increases
extracellular glutamate levels in
prefrontal cortex,
possibly via antagonism of
NMDA glutamate receptors on
GABAergic interneurons,
which results in disinhibition of
glutamatergic transmission
GABAergic neurotransmission
GABA – γ-aminobutirate
major inhibitory neurotransmitter in the central nervous system
(glycin: brainstem)
(Toxins that destroy synaptic SNARE proteins:
Tetanus toxin:
acts selectively to prevent glycine release
from inhibitory interneurons in the spinal cord,
causing excessive reflex hyperexcitability
and violent muscle spasms (lockjaw)

Botulinum toxin:
prevents acetylcholine release
prevents contraction
muscle relaxant
toxin-induced paralysis)
GABA A channel receptor
is a heteropentamer
It not only has a pore for Cl−
but also separate binding sites
for GABA
and several classes of
channel modulators

Chloride equilibrium potential is

more negative than
the resting membrane potential
→ chloride influx →
hyperpolarization

(The inset shows the presumed structure of one of the five monomers.
The M2 domain of each of the five subunits presumably lines the central channel pore.)
.
All drugs which increase inhibitory neurotransmission through
positive allosteric modulation of the GABAergic
neurotransmission
can cause the following actions in increasing doses:
• 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:
O
+ O
NH3
+
O NH3
O
C
O O Glutamic acid decarboxylase
(GAD) GABA
glutamate PLP (B6)

GAD – cytosolic, expressed only in GABAergic neurons (some in non-neuronal tissues?)

- (two isoforms with slightly different molecular weight (GAD65 and GAD67))
- inhibition → convulsion

Degradation of GABA:

GABA + α-ketoglutarate Succinic semialdehyde + glutamate

GABA transaminase (SSA)
(GABA-T)
PLP (B6) succinate
GABA-T – mitochondrial
GABA analog – (Vibagatrin, γ-vinyl GABA) → irreversible covalent binding to
GABA-T →
elevation of synaptic GABA → antiepileptic effect
 Not for
biochemistry exam

SV2A: synaptic vesicle glycoprotein 2A

[Link]
 GABA shunt
Glucose metabolism
GABA (α-ketoglutarate) transaminase

Glutamate
decarboxylase

Succinic semialdehyde dehydrogenase

 Neuron – glia interaction in the metabolism of GABA and glutamate

GABA transporters (GATs) – neurons

astrocytes (~ 20 % of released GABA is taken up by astrocytes)
- Na+-dependent
- functions against a GABA concentration gradient
- bidirectional
- GABA taken up by neurons is reutilized in transmission – in glia it is metabolized
- (GAT1 – primarily on presynaptic GABAergic terminals, GAT3 on astrocytic processes, GAT2
extrasynaptic region)
- GAT inhibitors - anticonvulsants
Neurochemistry International Volume 61, Issue 4 2012 546 - 558 [Link]
 Not for GABA A receptor, structure
biochemistry exam
 GABA receptors

GABAA receptor – ligand-gated chloride ion channels

produce rapid phasic (synaptic) and
tonic (extrasynaptic) inhibitory currents

targets of benzodiazepines (anxiolytics)

anaesthetics, ethanol Valium (diazepam)
(benzodiazepine)

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)

GABA A receptor – ligand-gated chloride ion channels Not for
biochemistry exam
rapid phasic (synaptic) and tonic (extrasynaptic) inhibitory currents

Brexanolone (allopregnanalone): neurosteroid, positive allosteric modulator, postpartum depression

Impulsiveness in teens?
 Not for
biochemistry exam GABA A receptor, pharmacology