excitatory transmission

Question 1

what are the 3 main types of ionotropic glutamate receptors defined by

Answer 1

the actions of the selective agonists AMPA, kainate and NMDA

Question 2

when a cell is at -60mV, what is the net flow of inward current mainly carried by

Answer 2

Na+ and Ca2+ ions entering the cell

Question 3

how are ionotropic glutamate receptor channels activated

Answer 3

selectively

Question 4

what is magnesimum

Answer 4

a voltage- and use-dependant blocker of the NMDA receptor associated ion channel

Question 5

what does the NMDAR conduct when activated

Answer 5

Na+, Ca2+ and K+

Question 6

how does the NMDAR channel open

Answer 6

it needs to be activated by glutamate or NMDA and by the co-agonist glycine

Question 7

what are blockers of the NMDAR ion channel

Answer 7

phencyclidine (PCP) and ketamine

Question 8

what do ketamine and PCP act as

Answer 8

clinically as an anaesthetic

Question 9

how is magnesium unblocked

Answer 9

through depolarising the cell

Question 10

what happens at +20mV

Answer 10

the net flow of current is outward - mainly by K+ ions leaving the cell
Mg2+ does not enter or block the cell

Question 11

what effect does Mg2+ have at -60mV

Answer 11

they block NMDA-evoked single channel openings in a concentration-dependant manner

Question 12

what effect does Mg2+ have at +40mV

Answer 12

no effect

Question 13

where does glutamate bind

Answer 13

GluN2 subunit

Question 14

where does glycine bind

Answer 14

GluN1 subunit

Question 15

what happens in the absence of glycine

Answer 15

glutamate does induce a current (due to activation of AMPARs)

Question 16

what happens in the presence of glycine

Answer 16

the current is greatly increase as now glutamate additionally activates NMDARs

Question 17

what is APV

Answer 17

a NMDAR selective receptor antagonist

Question 18

what is CNQX

Answer 18

an AMPAR antagonist

Question 19

explain the synergistic interplay of synaptic AMPAR and NMDAR at an excitatory synapse

Answer 19

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

Question 20

what facilitates NMDAR activation

Answer 20

high frequencies of presynaptic activation and stimulation of multiple glutamatergic input neurons

Question 21

what is EPSP

Answer 21

excitatory postsynaptic potential

Question 22

what increases postsynaptic depolarisation

Answer 22

repeptitive stimulation, or the stimulation of multiple glutamatergic inputs

Question 23

what is the structure of all ionotropic glutamate receptors

Answer 23

tetrameric assemblies of 4 subunits

Question 24

what are the subunits of NMDA

Answer 24

GluN1, GluN2A,B,C,D, GluN3A,B

Question 25

what are the subunits of AMPA

Answer 25

GluA1,2,3,4

Question 26

what are the subunits of kainate

Answer 26

GluK1,2,3,4,5

Question 27

what is the structural difference between ionotropic glutamate receptor subunits and ionotropic cys-loop receptor subunits

Answer 27

1 =tetramer - AMPA receptor - GluA1-4 2 = pentamer - nicotinic receptors, 5HT3 receptors, GABAa receptors, glycine receptors

Question 28

what are the majority of AMPARs

Answer 28

heteromers containing the GluA2 subunit

Question 29

what are AMPARs composed of

Answer 29

GluA1, 3 or 4 subunits

Question 30

what are AMPARs permeable to

Answer 30

Ca2+

Question 31

what are AMPARs blocked by

Answer 31

endogenous polyamines

Question 32

which subunit of AMPARs is critical in determining receptor function

Answer 32

GluA2

Question 33

what does incorporation of GluA2 subunits to AMPARs do

Answer 33

impairs Ca2+ permeability and prevents polyamine block

Question 34

what is the permeability of Ca2+ in AMPARs dictated by

Answer 34

the nature of a single AA located in the ion conducting pore glutamine Q = permeable arginine R = impermeable

Question 35

what is the GluA2 subject to, and what does this detemined

Answer 35

RNA editing whether the GluA2 subunit contains a Q or R residue at the ion channel

Question 36

in the adult, how much of the GluA2 is edited

Answer 36

95%

Question 37

what regulates calcium permeability

Answer 37

M2 Q/R-site

Question 38

what does spermine do

Answer 38

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

Question 39

what is an ionotropic glutamate receptor subunit composed of

Answer 39

ATD (amino terminal domain) CTD (caboxy terminal domain) M1-4 (transmembrane domains) S1-2 (ligand-binding domain)

Question 40

what are the majority of NMDARs composed of

Answer 40

GluN1 and GluN2 subunits

Question 41

what do NMDAR subunits have a similar topology to

Answer 41

the AMPA and kainate subunits

Question 42

what does the GluN1 subunit bind

Answer 42

glycine

Question 43

what does the GluN2 subunit bind

Answer 43

glutamate

Question 44

on the NMDARs, what is the asparagine residue (N) responsible for

Answer 44

site of Mg2+ block

Question 45

what are quantum dots (QD)

Answer 45

tiny semiconductor particles (nanometer)

Question 46

how are the movement of receptors in live neruones monitored

Answer 46

Using fluorescent quantum dots & high resolution microscopy

Question 47

what must be present for efficient synaptic transmission

Answer 47

postsynaptic receptors must cluster opposite presynaptic release sites

Question 48

what is the number of synaptic receptors dictated by

Answer 48

the interplay of reversible receptor stabilization &​ a dynamic equilibrium between pools of receptors in synaptic, extrasynaptic & intracellular compartments.​

Question 49

describe the AMPA receptor trafficking in and out of the postsynaptic density

Answer 49

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.

Question 50

what is the expression and location of AMPARs influenced by

Answer 50

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.

Question 51

what does LTP stand for

Answer 51

long term potentiation

Question 52

what is LTP induced by

Answer 52

a burst of high frequency stimulation (HFS)

Question 53

explain the process of AMPAR trafficking and LTP

Answer 53

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.​

Question 54

how does stabilising of AMPARs in the synapse occur

Answer 54

via an interaction of the C terminus ​with various interactor proteins & these interactors differ for GluA1 & GluA2.