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Glutamate Receptors

Glutamate Receptors mediate fast excitatory transmission in the CNS, permitting the influx of Ca & Na in neurons
Two functionally distinct types non-NMDA (fast) and NMDA (slow, Mg), distinct kinetics and conductance characteristics - shape of excitatory postsynaptic current
Three main classes, according to the agonist that selectively activates them NMDA: (-)AP5 AMPA: (+)kainate, less effective (-)CNQX & GYKI Kainate: (+)AMPA (-)CNQX
Glu-R subunits 9 for non-NMDA, 5 for NMDA
Non-NMDA-R subunits AMPA preferring subunits - GluR1-4 Kainate preferring subunits - GluR6&7 KA-1&-2 These two classes of subunits do not mix
AMPA-R subunits 1)function as both homomeric or heteromeric 2)tetrameric assemblies 3)GluR2 (Q/R) (GluR5&6)
NMDA-R subunits two families: NR1 & NR2 (NR2A,2B,2C&2D) 1) only as heteromeric assemblies of NR1- and at least one type of NR2 subunit
Topology 1)three membrane spanning regions (M1, M3&M4) 2)M2 is a re-entrant loop that forms pore 3)agonist binds between D1 and D2 regions, which resembles a clamshell
Tetramerisation - AMRA-R 1 pair of diametrically opposed GluR2 is the favoured conformation, which is required for Ca impermeability
Tetramerisation - NMDA-R Favoured NMDAR conformation (two NR1/NR2 dimers) is similar to that of AMPA-R
Gating mechanism 1)upon ligand binding, D1&D2 close, which further separate the dimers 2)NMDAR requires the binding of two Glu molecules to NR2 subunits, and two glycine to NR1 3)AMPR needs four Glu but less than four can partially open the channel
non-NMDA is classified into two groups based on Ca permeability and impermeability 1)Ca permeable AMPA-R is characterised by their inwardly rectifying I/V relationship, high single channel conductance, insertion triggered by acidification (during stroke)
Function of NMDA-receptor 1)long term potentiation of synaptic responses 2)excitotoxicity 3)epilepsy
Pharmacology of NMDA-R - modulation sites 1)glycine 2)Mg 3)porton 4)Zn
NMDA-R subunit diversity - localisation NR1 present throughout the CNS but NR2A-D are differentially distributed, and the expression changes with age, tailored to match the needs of a particular synapse at a given age
NMDA-R subunit diversity - functional properties distinct channel conductance, deactivation kinetics and sensitivity to Mg block different levels of Ca entry during NMDA activation
Properties of NMDA NR2 subunits table: NR2A has channel conductance, fast deactivation and highly sensitive to Mg block
Flip/Flop isoform Flop is predominant in adult, fast desensitisation
Q/R site Ca impermeability due to the presence of RNA-edited subunit (R at their Q/R sites) and the channels cannot be blocked by spermine
Functions of NMDA-R Fast synaptic transmission, long term changes in synaptic response, memory forming
Properties of NMDA-R largest conductance channel in CNS, inhibited by proton (protective mechanism)
Created by: JonLai