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Biomembranes > Excitatory neurotransmission > Flashcards

Excitatory neurotransmission Flashcards

1
Q

How can ionotropic glutamate receptors be studied

A
  • transfecting in the cDNAs encoding for their subunits into host epithelial cells, maintained in a cell culture
  • function of receptors can be investigated after 1-2 days by transiently applying agonist by breif pressure ejection from nearby pipette
  • whole-cell recording mode (clamped at -60mV)
  • inward flow of cations
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2
Q

Primary cation for AMPA and Kainate receptors

A

Na

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3
Q

What are the three main types of ionotriopic glutamate receptor and how are these defined

A
  • defined by selective agonist
  • AMPA, Kainate, NMDA
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4
Q

How to activate NMDA

A

requires both glutamate and co-agonist glycine, or D-serine

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5
Q

Effects of cell depolarisation

A

NMDARs become unblocked

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6
Q

Net flow of current at +20mV

A
  • mainly carried by K+ ions leaving the cell
  • Mg does not enter or block the cell
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7
Q

Net flow of current at -60mV

A
  • inward mainly carried by Na and Ca ions entering cell
  • Mg enters and blocks open channel
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8
Q

Impact that glycine has on current

A
  • in absence of glycine, glutamate does not induce a current due to activation of AMPARs
  • in presence of glycine, current is greatly increased as now glutamate additionally activates NMDARs
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9
Q

Where does glutamate bind

A

GluN2 subunit

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10
Q

Where does glycine bind

A

GluN1 subunit

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11
Q

How can the effect of magnesium on single NMDA receptors be studied using the outside-out patch technique

A
  • the traces show single channel events recorded at a negative holding potential of -60mV
  • at this potential magnesium causes rapid transitions in a concentration-dependent manner from the open state to the open but blocked state
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12
Q

What is APV

A

NMDR selective competitive antagonist

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13
Q

What is CNQX

A

AMPAR antagonist

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14
Q

Synergistic interplay of synaptic AMPA receptors and NMDA receptors at an excitatory synapse

A
  • neurally released glutamate activates AMPA receptors,
  • associated ion channel does not conduct due to magnesium blocking it
  • Na influx causes depolarisation of neuronal spine
  • if depolarisation is sufficient, it causes magnesium unblocking of NMDA receptor
  • appearance of a slow synaptic depolarisation
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15
Q

How does repetitive stimulation of multiple glutamatergic inputs increase the postsynaptic depolarisation

A

glutamate activation of synaptic AMPARs which unblock magnesium inhibition of NMDAR, reveals slow component of excitatory postsynaptic potential (EPSP)

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16
Q

Define temporal summation

A

the same presynaptic fibre fires action potential in quick succession, causing individual EPSPs to summate

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17
Q

Define spatial summation

A

two or more presynaptic inputs are simultaneously active causing their individual EPSPs to summate

18
Q

What are ionotropic AMPARs

A
  • tetramer
  • GluA1-4 subunits
  • majority are heteromers
  • calcium permeable
  • blocked by endogenous polyamines
  • critical in determining receptor function
19
Q

Incorporation of GluA2 subunit in ionotropic AMPARs

A

impairs Ca permeability and prevents polyamine block

20
Q

How is AMPAR permeability to calcium dictated

A

by the nature of a single amino acid located in the ion conducting pore

21
Q

RNA editing is responsible for

A

determining whether GluA2 subunit contains A or R residue at this key ion channel location

22
Q

GluA2Q

A

calcium permeable, blocked by polyamines

23
Q

GluA2R

A

calcium impermeable, not blocked by polyamines

24
Q

Which site regulates calcium permeability

A

M2 Q/R site

25
Q

What does spermine do

A
  • acts as intracellular AMPAR ion channel antagonist to block outward current carried by cations
  • only blocks GluA2-subunit lacking AMPARs and non-edited GluA2 AMPARs
26
Q

Evidence that S1 and S2 form ligand binding domain

A
  • show sequence homology to bacterial amino acid binding proteins
  • bacterial proteins bind amino acids between 2 lobes of a clam shell that are in a dynamic equilibrium between open and closed states - ligand binding stabilises the closed state
  • swapping S1 and S2 fomains between GluA3 and GluK2 causes appropriate changes to the agonist pharmacology -> forming agonist binding site
27
Q

Structure of the NMDA receptor

A
  • composed of GluN1 and GluN2 subunits
  • NMDAR subunits have similar topology to the AMPA and kainate subunits
  • GluN1 subunit binds Glycine/D-serine and the GluN2 subunit binds Glutamate
  • NMDARs have an asparagine residue (site of magnesium block)
28
Q

How can we monitor movement of AMPARs in neurons

A

using fluorescent quantum dots and high resolution microscopy

29
Q

What are quantum dots (QD)

A

tiny semiconductor particles

30
Q

What factors dictate the number of synaptic receptors

A
  • reversible receptor stabilisation
  • a dynamic equilibrium between pools of receptors in synaptic extrasynaptic and intracellular compartments
31
Q

For effective synaptic transmission, postsynaptic receptors must…

A

cluster opposite presynaptic release sites

32
Q

How are newly synthesized receptors transported in AMPA receptor trafficking

A

intracellularly in vesicles by molecular motors on microtubules

33
Q

Steps of AMPA receptor trafficking

A

1) transport of newly synthesised receptors
2) vesicle exocytosis in dendritic shaft
3) random movement of receptors on cell surface
4) diffusion trapping stabilises receptors
5) diffusing receptors internalised
6) endocytosed receptors can be recycled by exocytosis

34
Q

What can influence the expression and location of AMPARs

A

1) neuronal activity
2) exposure to acute and chronic stress
3) neurodegenerative disorders
4) by various drugs

35
Q

Describe Long Term Potentiation (LTP)

A
  • an electrophysiological correlate of learning and memory
  • involved “activity-dependent” changes in synaptic excitatory transmission mediatede by glutamate receptors
  • focus for research on improving synaptic plasticity and pathophysiology of neurodegenerative diseases
  • development of congitive-enhancing drugs
36
Q

How is LTP induced

A
  • high frequency theta burst stimulation (HFS) of the Schaffer collateral input from CA3 to the CA1 region
  • release lesion block, allowing calcium to enter
  • calcium binds to enzyme calmodulin kinase II, causing it to migrate
37
Q

Postsynaptic AMPA receptor trafficking and LTP

A
38
Q

How to assess learning and memory in rodents

A
  • role of GluA1-AMPARs in spatial memory
  • morris water maze
  • GluA1 mutant mice are imapired in this task and exhibit impaired hippocampal LTP
39
Q

AMPA receptors as therapeutic targets

A
  • cogntive disorders
  • development of novel “paid acting” antidepressants
40
Q

Huntington’s Disease

A
  • incurable neurodegenerative disease
  • caused by CAG repeats of the huntingtin gene, leading to a polyQ region in the huntingtin protein
  • characterised by motor dysfunction
  • mouse model exhibits impaired hippocampal LTP
  • AMPAkine CX929 improves impaired LTP and cognitive performance

Biomembranes (12 decks)

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