excitatory transmission Flashcards
what are the 3 main types of ionotropic glutamate receptors defined by
the actions of the selective agonists AMPA, kainate and NMDA
when a cell is at -60mV, what is the net flow of inward current mainly carried by
Na+ and Ca2+ ions entering the cell
how are ionotropic glutamate receptor channels activated
selectively
what is magnesimum
a voltage- and use-dependant blocker of the NMDA receptor associated ion channel
what does the NMDAR conduct when activated
Na+, Ca2+ and K+
how does the NMDAR channel open
it needs to be activated by glutamate or NMDA and by the co-agonist glycine
what are blockers of the NMDAR ion channel
phencyclidine (PCP) and ketamine
what do ketamine and PCP act as
clinically as an anaesthetic
how is magnesium unblocked
through depolarising the cell
what happens at +20mV
the net flow of current is outward - mainly by K+ ions leaving the cell
Mg2+ does not enter or block the cell
what effect does Mg2+ have at -60mV
they block NMDA-evoked single channel openings in a concentration-dependant manner
what effect does Mg2+ have at +40mV
no effect
where does glutamate bind
GluN2 subunit
where does glycine bind
GluN1 subunit
what happens in the absence of glycine
glutamate does induce a current (due to activation of AMPARs)
what happens in the presence of glycine
the current is greatly increase as now glutamate additionally activates NMDARs
what is APV
a NMDAR selective receptor antagonist
what is CNQX
an AMPAR antagonist
explain the synergistic interplay of synaptic AMPAR and NMDAR at an excitatory synapse
neurally released glutamate activates the synaptic AMPARs, but although glutamate also bind to NMDARs the associated ion channel does not initially conduct due to ion channel blockage from MG2+ which happens almost immediately
the Na+ influx caused by activation of AMAPR causes a depolarisation of the neuronal spine. if the presynaptic glutamatergic nerve fires at high frequenciesm or multiple glutamatergic inputs are stimulated then the depolarisation may be sufficient to cause MG2+ unblocking of the NMDA receptor and consequently the appearance of a slow prolonged synaptic depolarisation, mediated by NMDARs
high frequencies of presynaptic activity will favour NMDAR activation
what facilitates NMDAR activation
high frequencies of presynaptic activation and stimulation of multiple glutamatergic input neurons
what is EPSP
excitatory postsynaptic potential
what increases postsynaptic depolarisation
repeptitive stimulation, or the stimulation of multiple glutamatergic inputs
what is the structure of all ionotropic glutamate receptors
tetrameric assemblies of 4 subunits
what are the subunits of NMDA
GluN1, GluN2A,B,C,D, GluN3A,B
what are the subunits of AMPA
GluA1,2,3,4
what are the subunits of kainate
GluK1,2,3,4,5
what is the structural difference between ionotropic glutamate receptor subunits and ionotropic cys-loop receptor subunits
1 =tetramer - AMPA receptor - GluA1-4
2 = pentamer - nicotinic receptors, 5HT3 receptors, GABAa receptors, glycine receptors
what are the majority of AMPARs
heteromers containing the GluA2 subunit
what are AMPARs composed of
GluA1, 3 or 4 subunits
what are AMPARs permeable to
Ca2+
what are AMPARs blocked by
endogenous polyamines
which subunit of AMPARs is critical in determining receptor function
GluA2
what does incorporation of GluA2 subunits to AMPARs do
impairs Ca2+ permeability and prevents polyamine block
what is the permeability of Ca2+ in AMPARs dictated by
the nature of a single AA located in the ion conducting pore
glutamine Q = permeable
arginine R = impermeable
what is the GluA2 subject to, and what does this detemined
RNA editing
whether the GluA2 subunit contains a Q or R residue at the ion channel
in the adult, how much of the GluA2 is edited
95%
what regulates calcium permeability
M2 Q/R-site
what does spermine do
acts as an intracellular AMPAR ion channel antagonist to block the outward current carried by cations. it only blocks the GluA2-subunit lacking AMPARs and the non-edited GluA2 AMPARs
what is an ionotropic glutamate receptor subunit composed of
ATD (amino terminal domain)
CTD (caboxy terminal domain)
M1-4 (transmembrane domains)
S1-2 (ligand-binding domain)
what are the majority of NMDARs composed of
GluN1 and GluN2 subunits
what do NMDAR subunits have a similar topology to
the AMPA and kainate subunits
what does the GluN1 subunit bind
glycine
what does the GluN2 subunit bind
glutamate
on the NMDARs, what is the asparagine residue (N) responsible for
site of Mg2+ block
what are quantum dots (QD)
tiny semiconductor particles (nanometer)
how are the movement of receptors in live neruones monitored
Using fluorescent quantum dots & high resolution microscopy
what must be present for efficient synaptic transmission
postsynaptic receptors must cluster opposite presynaptic release sites
what is the number of synaptic receptors dictated by
the interplay of reversible receptor stabilization & a dynamic equilibrium between pools of receptors in synaptic, extrasynaptic & intracellular compartments.
describe the AMPA receptor trafficking in and out of the postsynaptic density
Newly synthesized receptors are transported intracellularly in vesicles by molecular motors on microtubules.
Vesicle exocytosis in the dendritic shaft.
Once at the cell surface, receptors move randomly.
The receptors are reversibly stabilized by diffusion trapping at the post-synaptic density (PSD) through interactions with intracellular & extracellular scaffold proteins.
Diffusing receptors internalized at extrasynaptic endocytic zones by clathrin-dependent endocytosis.
Endocytosed receptors can be recycled back by exocytosis.
what is the expression and location of AMPARs influenced by
neuronal activity – a basis for synaptic plasticity e.g. LTP.
exposure to acute & chronic stress.
neurodegenerative disorders e.g. Alzheimer’s Disease, Huntington’s disease.
by various drugs – e.g. ketamine, cocaine.
what does LTP stand for
long term potentiation
what is LTP induced by
a burst of high frequency stimulation (HFS)
explain the process of AMPAR trafficking and LTP
1) High-frequency stimulation relieves the magnesium block of the NMDAR to increase intracellular calcium allowing within seconds translocation of CaMKII (pink) to spines & subsequent phosphorylation of the γ2 and γ8 AMPAR auxiliary subunits.
2) This leads to increased binding of AMPARs to PSD95 resulting in their accumulation at the Post Synaptic Density (PSD) through diffusion-trapping.
3) In parallel, intracellular AMPARs, either newly synthesized, or from recycling compartments, are exocytosed within minutes of the stimulation, largely in the dendritic shaft, but also in the spine.
4) These AMPARs are delivered to the cell surface then replenish the extrasynaptic pool & further diffuse to the synapse.
how does stabilising of AMPARs in the synapse occur
via an interaction of the C terminus with various interactor proteins & these interactors differ for GluA1 & GluA2.
