PSC2002/L15 Ligand Gated Channels Flashcards
What is the difference between ionotropic and metabotropic glutamate receptors?
Ionotropic causes transient opening, cation influx and excitatory current
Metabotropic have modulatory role in synaptic transmission
What is the role of glutamate?
Principal excitatory neurotransmitter in vertebrate nervous system
Important roles in learning, memory, various disorders
Name 2 disorders associated with glutamate.
Epilepsy
Schizophrenia
Excitotoxicity
What are the 3 main classes of receptors?
AMPA, NMDA and kainate receptors
What is the difference between, AMPA, NMDA and kainate receptors?
AMPA & NMDA artificial
Glutamate & kainate activate all 3
NMDA & AMPA are specific agonists
KARs named by exclusion (kainate agonist; no effect on AMPA or NMDA)
Where is each ionotropic GluR (iGluR) found? (3)
AMPAR & NMDAR co-localised at synapses (fast transmission)
All can be synaptic & extrasynaptic
All can be pre-synaptic (autoreceptors) and post-synaptic
Where are GluRs mainly localised?
Postsynaptic sites
Dendrites of postsynaptic cell
Give an agonist of KAR, AMPAR and NMDAR. Which ions are they mainly permeable to?
Agonist glutamate
NMDAR - Ca2+
AMPAR & KAR - Na+
Describe the structure of iGluRs.
Multimeric protein complexes of 4 subunits (tetramer)
GABA and nAChRs have 5 subunits (pentamer)
Describe the structure of iGluR subunits.
3 transmembrane domains (TM1, TM3, TM4)
Re-entrant loop (TM2)
Describe AMPAR subunits GluA1-4.
Approx. 900aa, 68-73% identity
Can undergo 2 modifications (alternative splicing, RNA editing)
Can form homomeric and heteromeric channels
In heteromeric channels, presence of edited GluA2 determines the I-V curve and the Ca2+ permeability
Give 2 splice variants that affect receptor kinetics.
Deactivation - agonist unbinding leads to closure of channel, requiring removal of transmitter
Desensitisation - channel closes while agonist remains bound
What is a key difference between glutamate and ACh binding.
With glutamate present, receptor still closes
What is the difference between flip and flop in AMPA receptors?
Flip gives a sustained current
Flop gives a transient current
What does subunit composition of AMPA-R affect?
Ca2+ permeability
What is the relationship between P(Ca/Na) and relative abundance of GluA2?
Inversely proportional
Where are GluA2 receptors edited?
At the Q/R site
Describe editing at the Q/R site of AMPA receptors.
DNA of GluA2 codes for glutamine Q- swapped for arg R by editing of mRNA
+vely charged Arg renders channels containing Glu2 impermeable to Ca2+ (most but not all)
Implications for plasticity & toxicity
Where are Ca2+ permeable AMPARs found?
On all Bergman glial cells
Some hippocampal neurons
Some auditory neurons
What makes the GluA2 subunit impermeable to Ca2+?
Single aa in middle of transmembrane loop
Sticks to middle of pore and block relatively large Ca2+ ions
What is the rate of desensitisation proportional to?
Subunit composition and flip/flop variant
What modulates AMPAR trafficking and gating?
Auxiliary subunits
Describe kainate receptors.
Large presynaptic presence
Lower conductance than other GluRs
May have ionotropic & metabotropic actions
How was it found that kainate receptors may have combined ionotropic and metabotropic actions?
From pharmacological manipulation of 2nd messenger systems, supported by absence of effect in knockout animals
Block an effect of KAR activation by targeting 2nd messenger systems
Describe the structure of NMDA receptors.
Glycine site
Channel pore
Glutamate site
Zinc site
Proton site
What is required for NMDA function?
Glycine
Describe long-term potentiation. (4)
Very strong stimulus to single pathway - initial activity starts to depolarise the cell
Potentiation specific only to stimulated pathway
Long lasting increase in strength of synaptic connections
Fundamental mechanism for synaptic plasticity, thought to underlie learning and memory formation in the brain
Describe the AP5 rat experiment and what was found.
Rats put in a tank of water with a platform
Without AP5, swam around the platform
With AP5, swam all around the tank
AP5 impairs spatial memory
Give 3 general functions of Ca2+.
Cell division
Death
Structure
Motility Organelle motility
Gene expression
Give 3 neuronal functions of Ca2+.
Transduces electrical into chemical signals
Axon and dendritic elaboration and retraction
Synaptic vesicle retraction
Synaptic plasticity
Describe compartmentalisation of Ca2+ entry.
Ca2+ release into the presynaptic space required for vesicular release
Ca2+ also enters through postsynaptic channels- important for changing synapse strength
How are Ca2+ binding proteins localised?
Signal sequences or localisation signals that direct them to particular subcellular compartments
Describe Ca2+ transients.
Location and shape important
Message is interpreted by presence and sensitivity of local Ca2+ sensors
Describe synaptic NMDA activation and the downstream events that occur after this. (5)
Synaptic NMDA activation
CREB activation
BDNF gene expression
BDNF release
TrkB phosphorylation
What occurs after extrasynaptic NMDA activation? (2)
CREB inactivation (cAMP response element binding protein)
Loss of mitochondrial potential
