Excitatory transmission Flashcards
What are the 3 subtypes of ionotropic glutamate (D) receptors?
- AMPA
- KAINATE
- NMDA
what neurotransmitters is AMPA receptor sensitive to?
- Kainic acid
- AMPA
- NMDA
- glutamic acid
- glutamate, AMPA
what nt´s is Kainate receptor sensitive to?
- Glutamic acid
- kainic acid
what nt´s is NMDA receptor sensitive to?
- glutamic acid (response is very weak though)
- NMDA (also not a very sharp response)
which of the aforementioned glutamate receptors is blocked by Mg at -60 mV (voltage dependent block) ?
- NMDA receptor
conditions for NMDA receptor opening and generation of inward current
- binding of glutamate/NMDA and glycine co-activator
what are the (two) NMDA receptor co-agonists?
- Glycine
- D-serine
What are the (two) NMDA subunits and what do they bind?
- GluN1 binds co-agonist (glycine/D-serine )
- GluN2 binds glutamate
in terms of fast/slow EPSC, what type of EPSC does NMDA mediate?
- provide NMDA antagonist that inhibits slow EPSC
- slow EPSC
- APV NMDA receptor antagonist (only affects slow EPSC)
in terms of fast/slow EPSC, what type of EPSC does AMPA receptor mediate?
- provide name AMPA antagonist
- mediates fast EPSC component
- CNQX antagonist (only affects fast EPSC)
Glycine is a co-activator which is required for NMDA channel opening.
assuming all receptors present, what happens to the current if there is only glutamate (no co-activator) present?
Glutamate can still induce current due to AMPA receptor activation
What conditions can lead to overcoming of Mg blockage of NMDA receptors?
- high frequency presynaptic glutaminergic nerve firing
- multiple glutaminergic inputs
both lead to sufficient depolarization to cause Mg unblocking
What is a characteristic of NMDA receptor-mediated depolarization (after Mg blocking)
- slow, prolonged synaptic depolarization
what are some channel blockers of NMDA receptor?
- PCP
- ketamine
explain Temporal summation of excitatory postsynaptic potentials mediated by ionotropic glutamate receptors
- from a single presynaptic nerve fiber firing APs in quick succession, which summate
what is the structure subunit assembly of all ionotropic glutamate receptors?
- tetrameric
the GluA2 subunit of AMPA receptor has what characteristics?
- containsQ/R site responsible for Ca permeability/impermeability
- also determines whether AMPA is sucsceptible (Q present) to receptor blockage by polyamines
amino acid located in AMPA ion conducting pore that confers Ca permeability (present in non-edited GluA2 subunit)?
- Glutamine (Q)
Amino acid in ion conducting pore that confers ion IMpermeability?
Arginine (R)
in adults, which version of GluA2 is most common (95%)?
- GluAK
- GluA2
-GluAR
- GluAQ
-GluAR (edited version)
what occurs in gluA2 Q to R editing?
adenosinne deamination to inosine– read as guanisine
what spermine and what is its relation to AMPA receptors
- intracellular AMPAr antagonist that blocks outward cation movement
- acts on AMPArs lacking GluA2/non-edited GluA2 AMPArs (GluA2Q)
why are is the expression of Ca permeable AMPARs important in early development?
- mediates synaptic plasticity and long term potentiation
evidence for S1-S2 glutamate receptor subunit being the ligand binding domain?
- shows sequence homology to bacterial AA binding proteins
- ligand binding stabilizes the closed state
would S1/S2 domain swapping between GluA3 (AMPAR) and GluK2 (kainateR) affect agonist pharmacology ?
yes
what is the NMDA receptor equivalent of the AMPAR Q/R site at M2 subunit (hint: site of Mg2 block) ?
- asparagine residue
At a membrane potential of -60 mV
- in what direction is the net flow of current (and what ions are the drivers)?
- what is the state of Mg?
- net flow of current is inward carried by Na, Ca ions
- Mg enters cell–> blockage
at a membrane potential of 20 mV
- what is the directin of current flow (what ions are driving current)?
- state of Mg?
- net flow of current is outward carried by K
- Mg does not enter cell– no channel blockage
what AMPAr subunit (and its component) is responsible for mediating LTP?
- GluA1 subunit– interacts with essential proteins via C terminus
Pathophysiology of Huntingtons disease (hint: think about HD gene CAG140?
- think about what its effect on hippocampal LTP
- caused by CAG repeats of HD gene
- leads to polyQ region in polypeptide which causes impaired LTP
describe properties of AMPA receptors in terms of their movement in neurons
- highly plastic, change location in response to variety of stimuli
qualities of AMPA receptors that enourage efficient synaptic transmission (i.e. receptor stability, receptor pool state)
- reversible receptor stabilization– plastic
- dynamic equilibrium of receptor pool
mechanism of reversible stabilization of AMPA receptors (hint: occurs at post synaptic density)
- what components are involved in this mechanism
- diffusion trapping mediated by extra/intracellular scaffold proteins
what is the role of clathrin-dependent endocytosis in AMPA receptor trafficking?
- where does this mechanism take place?
- mediates AMPAr diffusion into PSD
- extrasynaptic endocytic zones
what induces Long term potentiation?
bursts of high frequency stimulation (HFS)
effect of HFS on NMDA receptors? on CaMKII translocation?
bonus: impact of CaMKII on Y2,Y8 auxiliary AMPAr SU´s?
- HFS relieves Mg block of NMDA receptors– inc. intracell. Ca
- subsequent CaMKII moved to spines— phosphorylation of AMPAr auxiliary SUs (Y2,Y8)
describe the role of AMPAr subunit GluA1 in LTP propagation
- CTD of GluA1 interacts with proteins to stabilize AMPAr
effect of swapping GluA1 CTD for GluA2 CTD on LTP?
- impaired LTP, spatial memory performance
Effect of ketamine/AMPA-kines on AMPAr?
- clinical applications?
- act as positive allosteric modulators
— potential antidepressant
