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Excitatory Ionotropic Receptors (Glutamate toxicity (Hypersensitive…
Excitatory Ionotropic Receptors
Glutamate Receptors
Metabotropic: mGluR(1-8)
mRNA splice variation (flip/flop)
Ionotropic: NMDA, AMPA, Kainate (substances not present, glutamate is endogenous activator)
RNA enzymatic Q/R editing
Intracellular C terminus
(TM2m re-entrant loop)
NMDA Receptor
Subunits
NR1: Single gene, 7 isoforms
NR2: Multiple genes, 4 subtypes
Antagonists
PCP, MK801
Non-competitive, non-polar (cross BBB) -> applications in glutamate toixicity
Not very selective -> many side effects -> not clinically useful
Overview
Tetramer (unlike gaba/glycine)
Two copies each of NR1 + NR2 +/or NR3
Glycine (NR1) is a co-agonist, required for activation with glutamate (NR2)
Mg ions block channel at -70mV (require AMPA depol.)
Permeable to Ca and Na
AMPA mediated depolarization activates NMDA
Pathway activation (Ca2+)
NO formation (cerebral blood flow, neurodegeneration, synaptic plasticity)
PLA2 (gene expression)
CaMKII (changes in synaptic efficacy)
AMPA Receptor
GluR1-4 subunits
Kainate Receptor
GluR5-7 and KA-1/2 subunits
Glutamate toxicity
Hypersensitive receptors
Causes axon-sparing lesions
Abnormally high levels
NMDA Mediated: activates endonucleases -> DNA damage -> PARP activated -> consumes NAD+ and induces AIF release from mitochondria
High Ca2+ in mitochondria -> energy failure + H+ acidosis
Ca2+ activates proteases (calpain)