Ketamine - glutamate neurotransmission Flashcards
fast transmission utilise which type of receptors
ligand gated ion channel
behaviours that use fast transmission
sight
reflexes
audition
fast neurotransmitter examples
glutamate
GABA
Glycine
glutamate
= fast, excitatory
makes up 90% of synaptic communications in the brain
history and first evidence of glutamate
Hayashi 1954
David curtis and watkins 1959
Hyashi 1954
induced seizures in dogs and monkeys
David Curtis
Watkins
1959
used cats and found first real evidence that Glu was excitatory
used microelectrophoretic techniques
dendritic spines
narrow neck and wider head with PSD
where the synapses are made between dendrite and post synaptic membrane
PSD
post synaptic density
5 core components of neurotransmitter system
1 - molecules to synthesise NT 2 - transporters for NT entry into cells 3 - transporters for NT entry into vesicles 4 - receptors activated by NT 5 - molecules to terminate NT action
glutamate biosynthesis
e.g. glutamine precursor + H2O –> Glu + NH3
is glutamate an essential amino acid
no
non essential
not necessary in diet
transporters to get glutamate into cells
EAAT 1-5
main transporter to get glutamate into cells
EAAT2
mediates 90% of Glu uptake into cells
transporters to get glutamate into vesicles
VGLUT 1-3
receptors activated by glutamate
AMPA
NMDA
Kainate
mGluRs
termination of glutamate activity
diffusion
uptake into cells via EAAT mediators
3 components of tripartite synapse
neuronal terminal
post-synaptic membrnae
astrocyte
why are astrocytes important
its important not to have too much Glu floating around to prevent over activation
glutaminase
enzyme
converts glutamine into glutamate
ionotropic Glu receptor features
ligand gated ion channel
rapid tranmission
metabotropic Glu receptor features
GPCR
signal via 2nd messenger cascades
7TM subunits
3 families of ionotropic Glu R
AMPA
Kainate
NMDA
how many possible different subunits in AMPA R
4
tetrameric
how many possible different subunits in Kainate R
5
how many possible different subunits in NMDA R
7
GluA1 means
Glutamate AMPA receptor subunit 1
GluN1 means
Glutamate NMDA receptor subunit 1
Q/R site
determines Ca2+ permeability of GluA2
AMPA R permeability to Ca2+
nearly all AMPA R are Ca2+ impermeable
most contain GluA2 subunits
when are AMPA R permeable to Ca2+
in the absence of GluA2 subunits
competitive antagonist
NBQX
non-competitive antagonist
Telampanel
positive allosteric modulators
increase glutamate affinity
make desensitisation less effective
Ampakine
positive allosteric modulators of AMPA receptors
Ampakine effect
increases Glu signalling with same conc of Glu
enhances currents through AMPA R channels
day to day fundamental Glu signalling
via AMPA
Domoate
domoate is kainite receptor agonist
precusor for domoic acid –> environmental toxin
effects of domoic acid
crosses BBB
causes loss of short term memory, motor weakness, seizures, death
NMDA receptor activation
only under special circumstances
NMDA structure
heterotetramer
2 x GluN1
2 x GluN2
NMDA receptor properties
high Ca2+ permeability
Mg2+ blocks the channel at resting potentials
glycine necessary co-agonist
NMDA at -35mV
depolarising potential from AMPA R
Mg2+ block removed from pore
lots of Na can flow through
examples of drug binding sites on NMDA receptor
glutamate agonist/antagonist site
glycine agonist/antagonist site
allosteric modulators
pore blockers
glycine agonist
D-serine
released by astrocytes
what does the affinity of glycine for GluN1 depend on
the type of GluN2
glycine antagonist function
prevents glycine co-activation of NMDA receptor
example of glycine antagonist
kynurenate
what are NMDA channel blockers
uncompetitive NMDA R antagonists
examples of uncompetitive NMDA R antagonists
ketamine
PCP
high affinity NMDA channel blocker
PCP (phencyclidine)
effects of ketamine
blocks NMDA R with low affinity
induces sedation, immobility, analgesia
damages bladder
phencyclidine
PCP
high affinity uncompetitive antagonist of NMDA R
blocks the channel
effects of PCP
hallucinogen
anaesthetic
difference between AMPA and NMDA EPSCs
NMDA EPSC is much longer-lasting
once Glu is bound to NMDA, takes longer to fall off
EPSP mediated by NMDA R
slow-rising, long-lasting excitatory
via Na+ and Ca2+
definition of synaptic plasticity
the ability to change the strength of synaptic connections and consolidate new pathways in the CNS
how do you induce LTP
high frequency (100Hz for 1 second) stimulation of hippocampal tissue slice specifically schaffer collateral pathway
examples of NMDA R-dependent hippocampal plasticity
LTP
LTD
effect of LTP
long-lasting increase in EPSP amplitude
stimulating LTD
1 Hz for 15 mins
effect of LTD
long lasting decrease in EPSP amplitude
pathophysiology of NMDA R
excitotoxicity
epilepsy
transmission of pain responses
schizophrenia
excitotoxicity
over activation of NMDA
too much glutamate signalling
excessive entry of Ca2+
neuronal cell death
NMDA in epilepsy
NMDA Rs involved in development of seizures
anticonvulsant activity of NMDA R antagonists correlates with their affinity for NMDA R
NMDA in transmission of pain response
NMDA Rs are expressed on sensory neurons
maladaptive plasticity
NMDA and schizophrenia
hypofunction of NMDA R
e.g. caused by PCP
causes psychotic episodes
2 subclasses of glutamate transporter
EAAT (into cell)
VGLUT (cell cytoplasm –> vesicles)
3 kainate receptor agonists
kainate
glutamate
domoate