Glutamate neurotransmitter

The metabolic roles of Glu

Glutamate (aspartate)The most important excitatory neurotransmittersLearningNeuronal developmentEpilepsyIschemiaNon essential aa-s do not penetrate the BBBMetabolites + neurotransmitters separate pool

Glutamatergic neurotransmissionGLT-1GLAST

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

Synaptic AMPA & NMDA receptorsAz AMPA & NMDA receptors colocalization AMPA activation depolarization inhibition by Mg2+ on NMDA receptor NMDA activation

The synaptic AMPA & NMDA receptors

AMPA activation depolariztion Mg2+ inhibition NMDA NMDA activation Fast desensitization

NMDA receptor (Glu & Asp receptor)Strictly controlledActivators:Glu and Gly co-agonistsPoliaminesInhibitors: Mg2+Zn2+H+inhibit ion-fluxVoltage-dependent block of the open channelpH 6 complet inhibitionHa van GluR2 subunitNincs Ca2+ permeabilits

NMDA receptorActivation Na+, K permeability Ca2+ influxtransient activation of Ca2+-dependent enzymesCa2+-CAM dep. prot. kinz II.CalcineurinPKCPhospholipase A2PLCNO synthaseEndonucleaseSynaptic plasticityHippocampusLTPLTD

Metabotrop glutamatergic receptorsmGluR- pre- and postsynaptic localizationModulationIonic channels L-N type Ca2+ channels K+-channel Receptors(NMDA, AMPA, DA, GABA, NA) or PresynapticGABA, Glu transzm (Ca2+channel inhibition)

Increased glutamateergic activity neurotoxicIschemiaNeurodegenerationEpileptiform seizures

Neurotransmitter uptake systems in the presyzinaptic glutamatergic neurons

Neurotransmitter symport systemsNa-dependent reuptake in the axon terminl (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 synapseHinyuk: [Glu]e Lethal convulsions (mice)

Neurotransmitter symportsMany isoforms in neurons

1 < Na+ influx - depolarizationanion 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

AMPA & NMDA receptors in synapses

Initial steps of ischemic brain damage

Excitotoxic effect of Glu in ischemia

Ca2+ homeostasisCa2+ pathological effects :

- decrease in m decreased ATP production - increased ROS prodn- permeability tranzition pore openingIn mitochondriaCa2+ physiological effects

PDH ICDH KGDH activation

NADH increased ATP productioin-180 mV