NEUR3001 Lecture Notes - Lecture 2: Cytoskeleton, Phospholipid, Inositol

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4 Jul 2018
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Central Synaptic Transmission: Postsynaptic
Organisation of Excitatory Synapses
1. Structure of Excitatory Synapses
1.1. Chemical Synaptic Transmission in CNS
Synaptic contacts formed by presynaptic terminals & postsynaptic membranes separated by synaptic cleft
NT packaged within synaptic vesicles fuses with presynaptic plasma membrane @ active zone exocytosis
NT diffuse across synaptic cleft, bind & activate postsynaptic receptors causes opening of ion
channels/activation of NT response (hyperpolarisation)
Glutamate & GABA receptors are differentially targeted to the postsynaptic membrane
Postsynaptic organisation of excitatory & inhibitory synapses varies & consists of different scaffolding
proteins that anchor receptors
@ excitatory synapses, postsynaptic specialisation exists dendritic spine
1.2. Structure of an Excitatory Synapse
GABAR
AMPAR/
NMDAR
Packed with scaffolding
proteins & receptors
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2. Postsynaptic Density
composed of many proteins, including scaffolding proteins
2.1. PDZ Domain
Modular domain with ~90 AA found in 3 proteins: PSD-95, Dig-1 & ZO-1
Highly abundant protein-protein interaction module commonly found in multi-domain scaffold proteins
Canonical PDZ domains bind to 3 types of PDZ binding motifs located at extreme C-terminus of a protein
Some PDZ domains have promiscuous interaction with target proteins, including binding to internal
peptides/internal hairpin structures
A subset of PDZ domains interact with lipids (phosphoinositide)
PDZ sits nicely on PSD
2.2. Molecular Organisation of PSD
Highly concentrated with AMPAR & NMDAR
PSD-95 verticle while other scaffolds (GKAP & Shank) horizontal
Loss of PSD-95 expression alters molecular organisation of PSS-95 patchy loss of AMPAR (blue) but not
NMDAR (cyan)
2.3. Membrane-Associated Guanylate Kinase (MAGUKs)
Important scaffolding protein in
PSD
4 major members: PSD-93, PSD-
95, SAP-97 & SAP-102
Major role in Synaptogenesis &
synaptic maturation during
development / synaptic
plasticity in adult
PSD-95 anchors AMPAR &
NMDAR on PSD but
manipulating PSD-95 shows
specific effect on AMPA current
MAGUK proteins can
compensate for loss of others to
a certain extent
Serine/Therine
Glutamate/Aspartate
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3. Ionotropic Glutamate Receptors: AMPAR
Mediates 70-80% of the fast excitatory synaptic transmission in CNS
4 AMPA subunits: GluA1-4 encoded by 4 genes (GRIA1-4)
Tetramers formed by 2 dimers
Mainly conduct Na+ & K+ but GluA2 lacking AMPAR also permeable to Ca2+
↑V=↑A
3.1. AMPAR-Interacting Proteins
Carboxy-tails of AMPAR subunits contain many regulatory signals, including protein0protein interactions &
post-translational modifications
These proteins are important in controlling biosynthesis, vesicular transport, membrane trafficking, synaptic
targeting & diffusion of AMPARs
3.2. Auxiliary Subunits of AMPAR
Many transmembrane proteins & secreted proteins co-assemble & stably associated with AMPAR pore-
forming GluA1 & 2 subunits
Affects multiple aspects of receptor pharmacology, functions, biogenesis & subcellular trafficking/targeting
Main auxiliary units: TARP, CNIH, CKAMP
Transmembrane AMPAR Associated Proteins (TARP)
o TARP I type 1 PDZ binding motif e.g. γ-2, γ-3, γ-4, γ-8
o TARP II atypical PDZ ligand e.g. γ-5, γ-7
o Differentially expressed throughout brain regions
o Slow the decay kinetics of AMPAR
o Regulate AMPAR surface expression & synaptic targeting through cytoplasmic domain
o Stargazer mouse (mutated stg gene) exhibits ataxia & absence epilepsy
Type 1 motif binding
Type 2 motif
binding
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Document Summary

Orga(cid:374)isatio(cid:374) of e(cid:454)(cid:272)itator(cid:455) s(cid:455)(cid:374)apses: structure of excitatory synapses. Glutamate & gaba receptors are differentially targeted to the postsynaptic membrane. Postsynaptic organisation of excitatory & inhibitory synapses varies & consists of different scaffolding proteins that anchor receptors. @ excitatory synapses, postsynaptic specialisation exists dendritic spine. Packed with scaffolding proteins & receptors: postsynaptic density. Composed of many proteins, including scaffolding proteins. Glutamate/aspartate: some pdz domains have promiscuous interaction with target proteins, including binding to internal peptides/internal hairpin structures, a subset of pdz domains interact with lipids (phosphoinositide, pdz sits nicely on psd. Molecular organisation of psd: highly concentrated with ampar & nmdar, psd-95 verticle while other scaffolds (gkap & shank) horizontal. Loss of psd-95 expression alters molecular organisation of pss-95 patchy loss of ampar (blue) but not. 95, sap-97 & sap-102: major role in synaptogenesis & synaptic maturation during development / synaptic plasticity in adult, psd-95 anchors ampar & 2 dimer forms subunit e. g. glua1 & 2 most abundant.

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