Lecture 19; Synaptic Plasticity 1 Flashcards
Describe AMPA regulation;
LTP and LTD reflect bi-directional and symmetrical regulation of AMPARs:
Therefore; Bidirectional receptor regulation in plasticity
Describe the localisation of post synaptic receptors;
AMPA and NMDA are localised to the tip of the post synaptic clefts, NOT on the sides
At a very specific part of the membrane as is the PSD
What is located under the post synaptic membrane?
The post synaptic density (PSD)
Describe the PSD in excitatory neurons;
In excitatory neurons the PSD is thick (hallmark feature)
I.e post synaptic excitatory glutamatergic neurons
Thinner in inhibitory PSDs
Describe the PSD;
- Specialisation of the postsynaptic membrane - high concentration of proteins–estimate ~1000 proteins
- Made up of receptors, scaffolding proteins, transduction proteins, trafficking proteins
How can you differentiate the post synaptic density from the pre synaptic density?
The presynaptic density has lots of vesicles containing neurotransmitter
Describe some of the key properties of PSD proteins;
- Almost all have multiple domains
- Domains act as protein-protein binding sites in a reversible manner creating a plexus
- Share properties
Binding is essential for the density
What is the most famous PSD protein?
PDZ domains
Whats so special about the PDZ domain?
–PDZ-domains bind to each other
–Present in most PSD proteins
–Bind the C-terminal tails of glutamate receptors
What is the equivalent PSD on the presynapse?
Proteins form an action site on the presynapse
What do the PSD protein domains allow?
- Allowing protein protein interactions
- Protein receptor interactions
- Protein linking back to cytoskeletal interactions
What is the design of the PSD for?
Intricate design to allow high density of proteins and to traffic receptors to the membrane
What binds to the glutamate receptors?
C terminal of the glutamate receptors contains a PDZ domain and binds PDZ in the PSD.
Stabilises the receptors
What are some key PSD proteins?
SAP97
GRIP
SHANKS
Describe SAP97;
Synapse Associated Protein 97kDa
Binds directly to both AMPA and NMDA receptors (rare to bind both)
What is the function of SAP97 according to biochemistry?
- trafficking receptors from the soma to the synapse
* Maintaining the structural integrity of the PSD through protein-protein interactions
What is unique about SAP97?
It traffics both AMPA and NMDA but in two distinct ways (essential for plasticity)
What makes receptor trafficking difficult?
neurons are polarised
Describe the binding of SAP97;
PDZ domains important in protein:protein interactions
AMPA PDZ one of SAP97
NMDA PDZ two of SAP97
What does GRIP consist of?
Entirely PDZ domains (only one)
What is the function of GRIP?
-GRIP is known to be critical in the removal of AMPA receptors from the postsynaptic membrane during LTD
What are SHANKS also known as?
A master regulator. Critical protein in PSD. Binds many other proteins
Can bind directly or indirectly to glutamate receptors
What is special about shanks?
It has the most binding partners.
Multidomain
Where are shanks location in the PSD?
-Lie in the middle of the PSD and form a scaffold across the PSD
SAM domain is important for this parallel structure
Why are shanks known as the master regulators?
-Due to their ability to form complexes with receptors, signalling molecules and the cytoskeleton, Shanks are thought of as “master regulators” of the synapse
What are the five possible roles of PSD proteins?
1) Structural Role
2) Trafficking receptors to the synapse
3) Inserting receptors into the membrane
4) Signaling molecules
5) Removing receptors from the membrane
How do PSD proteins play a structural role?
–Through domains PSD proteins can interact with each other and form tight bonds that link to actin cytoskeleton
Maintains structure when receptors are added or removed
Very specific linkages for this
How do PSD proteins play a trafficking role?/ describe receptor trafficking
- Receptors are synthesised in the soma and assembled in the ER and Golgi
- Significant trafficking of glutamate receptors must occur along dendrites to supply synapses
Chaperone proteins!
Give a specific example of receptor trafficking;
For example: SAP97 binds simultaneously to the microtubule motor Kif1b and to the GluR1 subunit of the AMPA receptor
Describe how PSD proteins help insert receptors into the membrane;
- AMPA receptors are thought to be ‘stored’ in vesicles in the spine head
- A PSD protein termed ‘Stargazin’ is thought to bind AMPA receptors and direct their insertion into the postsynaptic membrane
- AMPA receptors then become ‘stabilised’ at the PSD through interactions with multiple PSD proteins that form complexes around the receptors
Are receptors inserted directly into the membrane?
No most move across via lateral diffusion and form stabilising interactions with the PSD
How do PSD proteins act as signalling molecules?
- Many PSD proteins act together to form signalling complexes that operate downstream of glutamate receptors
- Distinct PSD protein complexes are likely assembled around each subtype of receptor. Therefore each receptor class can transmit different signals into the postsynaptic cell.
What property of the PSD allows it to be a signalling complex?
Protein:Protein domains can have IC signalling capacity therefore creating signalling complexes.
How does the PSD aid receptor removal?
- Glutamate receptors must be uncoupled from the PSD proteins that are stabilising it in the membrane
- Receptors can then be removed via endocytosis
What determines how the receptors are removed?
Evidence suggests that post-translational modifications of AMPA receptors regulates whether ‘stabilising’ or ‘endocytic’ PSD proteins can bind to the AMPA receptor
•Protein phosphorylation of the GluR2 subunit of the AMPA receptor dictates whether it can bind the endocytic protein GRIP.
