Glutamate neurotransmitter

The metabolic roles of Glu

Glutamate (aspartate)

The most important excitatory neurotransmitters

LearningNeuronal developmentEpilepsyIschemia

Non essential aa-s – do not penetrate the BBBMetabolites + neurotransmitters – separate pool

Glutamatergic neurotransmission

GLT-1

GLAST

NDMA – N-metil-D-aspartateAMPA – -amino-3-hidroxi-5-metil-4-izoxazol propionic acid

Synaptic AMPA & NMDA receptors

Az AMPA & NMDA receptors colocalization

AMPA activation → depolarization → inhibition by Mg2+ on NMDA receptor↓ →NMDA activation

The synaptic AMPA & NMDA receptors

AMPA activation depolarizátionMg2+ inhibition NMDA

NMDA activation

Fast desensitization

NMDA receptor (Glu & Asp receptor)

Strictly controlledActivators:

Glu and Gly co-agonists

Poliamines

Inhibitors: Mg2+

Zn2+

H+

inhibit ion-flux

Voltage-dependent block of the open channel

pH 6 complet inhibition

Ha van GluR2 subunitNincs Ca2+ permeabilitás

NMDA receptorActivation Na+, K permeability Ca2+ influx

↓↓transient activation of Ca2+-dependent enzymesCa2+-CAM dep. prot. kináz II.CalcineurinPKCPhospholipase A2

PLCNO synthaseEndonuclease

Synaptic plasticityHippocampus

LTPLTD

mGluR- pre- and postsynaptic localization

ModulationIonic channels L-N type Ca2+ channels K+-channel –

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

PresynapticGABA, Glu transzm (Ca2+channel inhibition)

Metabotrop glutamatergic receptors

Increased glutamateergic activity neurotoxic

Ischemia

Neurodegeneration

Epileptiform seizures

Neurotransmitter uptake systems in the presyzinaptic glutamatergic neurons

Neurotransmitter symport systems

Na-dependent reuptake in the axon terminál (secondary active transport)

Two subfamilies

*GABA, glicin, noradrenalin, dopamin, serotonin transporters

12 transzmembrane regions

Na (Cl-) dependent transporter

*Na+-(-K+) dependent glutamate transporter (5 isoforms)GLAST (glutamate-aspartate transporter)

GLT-1 Astrocytes

Glu clearance – from the synapse

Hiányuk: [Glu]e

Lethal convulsions (mice)

Many isoforms in neurons

1 < Na+ influx - depolarization

anion efflux – intracellular acidification

[Glu]szinapszis < 0,6 uM

(10 mM brain, 2-3 uM extracellular)

Anoxia, long-lasting depolarization – reversal of function

Glu release

Toxic

Neurotransmitter symports

AMPA & NMDA receptors in synapses

Initial steps of ischemic brain damage

Excitotoxic effect of Glu in ischemia

Ca2+ homeostasis

Ca2+ pathological effects :

- decrease in m

↓

decreased ATP production

- increased ROS prodn

- permeability tranzition pore opening

In mitochondria

Ca2+ physiological effects

PDH

ICDH

KGDH activation

↓

NADH ↑

↓

increased ATP productioin

-180 mV