2. Ch 8 Glutamate GABA Flashcards
What where is glutamate and synthesis
glutamate is ionized form of glutamic acid
all neurons and glia have high amts glutamate
glutamatergic neurons have higher conc., segregate signaling glut and protein glut
Glutamine -> Glutamate (uses Glutaminase)
vesicular glutamate transporters
VGLUT 1/2/3
specific marker of glutamatergic neurons as only found there
Glutamate Synaptic Transporters locations
Excitatory Amino Acid Transporters
located in neurons and astrocytes
EAAT 1-5
1/2 in in glia, astroctyes do 90% uptake in brain
4 - purkinje cerebellum
5 - bipolar retina
3 - post synaptic buffer nearby glutamate, modulate excitatory transmission and plasticity. prevent overstim
EAAT2 KO
in astrocytes
KO = shorter life, more susceptible to seizures
EAAT2 Downregulation
downreg in ALS = too much glutamate
treat with NMDA anatagonist for ALS (block overstim/excitotoxicity)
treat with EAAT2 upregulation (less glut), improves motor function and life
EAAT1 Mutations
EAAT1 in cerebellar glia
mutant = less expression = less glut uptake
= hyperexcitability and cell death
causes episodic ataxia (no balance) due to cell death
Metabolic Partnership of glutamate and glutamine
astrocytes converts glutamate to glutamine with glutamine synthetase
glutamine goes back to neurons via glutamine transporters
this way the brain can story glutamate in a safe form (avoid excitotoxicity)
2 kinds of glutamate receptors
ionotropic - fast signaling
metabotropic - second messengers slower signaling
ionotropic receptors AMPA
AMPA, Kainate, NMDA. each has four subunits
AMPA and Kainte let in Na
NMDA let in Ca and Na (coincidence detector and source of excitotoxicity)
NMDA receptors for glutamate
permeable to Na and Ca (ionotropic)
both glutamate and glycine/D-serine (made by serine racemase in astrocytes) must bind at same time (co-agonists)
Voltage-dependent magnesium block - Mg expelled when membrane depol from nearby AMPA receptors
“coincidence detector” = glutamate and cell depol
Metabotropic receptors for glutamate
mGluR 1-8
2,3,4,6,7,8 = inhibit AC with Gi. Presynaptic autoreceptors
1,5 = actiavte PLC with Gq. postsynaptic and does LTP/D
Glutamate and Schizophrenia
NMDA receptor Hypofunction Hypothesis
NMDA antagonists (PCP and ketamine are non comp antagonists) induce pos/neg/cog schizo symptoms (in healthy and exacerbate schizo)
PCP and ketamine are psychotomimemtics (do psychosis)
NMDA receptor deficit in schizo
NMDA reduced expression in schizo mice, and social isolation
NMDA KO = die
Domoic Acid
Kainic acid (kainate rec.) analog
3x potency of Kainic acid
made by marine algae, neurotoxin for amygdala that caused aggro in birds (hitchcock birds)
LTP mechanism
influx of Ca2+ in NMDA activates CAMK2
this phosphorylates existing AMPA and creates more AMPA rec. = inc. sensitivity to glutamate
CAMK2 KO = learn less efficiently and reduced EPSP from tetanus
NR2B subunit NMDA
Overexpressed NR2B subunit in Doogie mice
made more efficient learning, ehnanced LTP
also enhanced sensitivity to pain, NMDA in pain
Fragile X Syndrome and LTD
mGluR5 activation = LTD
mGluR5 antagonist (CTEP) = inhibit rec. and reverses LTD
Fragile X = lose gene that inhibits mRNA translation, too much protein = LTD. Block mGluR5 to reverse effects of FMRP gene loss. normal plasticity
Glutamate Excitoxicity
what is it and where damage
prolonged depol = cell death
injecting monosodium glutamate MSG = damage arcuate nucleus in hypothal
damage at POST SYN sites, not terminals
Mechanism of glutamate excitoxicity
Ca2+ influx activates molecules that degrade cell protein/membrane
necrosis due to lysis
happens when brain trauma injury bc causes massive release of glutamate
treat with NMDAR antagonists
NMDAR antagonists might treat Alzheimers (caused by glutamate excitiatory)
GABA synthesis
synthesized ONLY by GABAergic neurons, only functions as NT, only found in CNS
Glutamate -> GABA (using glutamic acid decarboxylase GAD)
GABA vesicular transporters and synaptic transporters
VGAT moves GABA into vesicles
Removed from cleft by GAT 1/2/3
GAT 1/2 = neurons and astrocytes
GAT 3 = astrocytes
Metabolism of GABA in neurons and astrocytes
In GABAergic neurons = metab. to glutamate (so can go back to GABA) and succinate by GABA-aminotransferase GABA-T
In astrocytes = metab. to glutamate by GABA-T, glutamate converted to glutamine by glutamine synthetase, glutamine goes back to GABAergic neurons through transporters
GABA two types receptors
GABAa = ionotropic
GABAb = metabotropic
GABAa Receptor
ionotropic
allows Cl- to move inside cell (inhibitory)
five subunits, pentamer (over 20 subunits = lots of heterogeneity in pharmaco properties)
Bendoziazepines and Barbituates
both bind to GABAa rec. at positive allosteric modulatory sites (not the ligand site)
potentiate effects of GABA on the rec.
BDZ = increases potency of GABA, can’t open channel w/o GABA, only modulatory
Barbituates = very high doses can open channel w/o GABA = allosteric agonist, lethal
Non-BDZ compounds
Z-drugs
dissimilar chemical structure to BDZs
Similar pharamcodynamics (same benefit/side effect) - positive allosteric modulator at BDZ site on GABAa rec.
Gabapentinoids
Used for epilepsy/pain/bipolar
GABA analogues (similar chem structures to GABA)
does NOT bind to GABA rec. or have any GABA-ergic function
inhibits subunit of VGCC to mediate effects
GABAb Receptors
metabotropic
not activated by BDZs or Barbs
requires two subunits (unlike any other GPCR)
Autoreceptors = inhibit VGCC or inhibit cAMP formation
As PostSyn = inhibit cAMP formation or open K channels (e.g. Baclofen is a muscle relaxant and is used for ASD, GHB is for narcolepsy date-rape drug
