Structure & function of glutamate receptors
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Transcript of Structure & function of glutamate receptors
Structure & function of glutamate receptors
Bi/CNS 150 Lecture 8 Wednesday October 14, 2013 Structure &
function of glutamate receptors Henry Lester Chapter 10 ( )
Superfamilies of ligand-gated ion channels that are synaptic
receptors
A. ACh, Serotonin 5-HT3, GABA,(invert. GluCl, dopamine,
tyrosine)receptor-channels Most ^ Modified from Figure 10-7 a
favorite model system for neuroscience
The Hippocampus: a favorite model system for neuroscience The
tri-synaptic pathway See also Chapter 67 Electron micrograph of
hippocampal synapse
Map of micrograph to the left A postsynaptic density, with a
cartoon of important proteins There are also G protein-coupled
glutamate receptors
Ionotropic Glutamate Receptors: 3 transmembrane helices plus a
selectivity filter per subunitx 4 subunits Selectivity Filter NMDA
receptors have a large cytoplasmic tail There are also G
protein-coupled glutamate receptors (not shown here) Figure 10-8 3
families of Ionotropic Glutamate Receptors are named by their
selective synthetic agonists
Family Subunits AMPAGluR1-4 (Most areGluR1/2 or GluR2/3) Kainate
GluR5-7 NMDA NR1* (*obligatory)NR2A or B or C or D Ion Selectivity
of Glutamate Receptor Channels
AMPA and Kainate Receptors: With GluR2 subunit: permeable only to
K+ and Na+ Without GluR2 subunit: Ca2+-permeable (and K+, Na+) NMDA
Receptors: Permeable to K+, Na+, Ca2+ RNA Editing Determines Ca2+
Permeability of AMPA Receptors #1
Q= R= Transcribed codon: CAG Edited codon: CIG Right: Modified from
Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999) RNA
Editing Determines Ca2+ Permeability of AMPA Receptors #2
Fig. 10-9 NMDA Receptors Are composed of NR1 subunits and four
different NR2 subunits; NR2A, NR2B, NR2C, and NR2D. They contain
two NR1 subunits, and a pair of NR2 subunits, which can be
identical or mixed. NR1 subunits are similar in size to GluR1-4;
they are necessary to form the receptor channel, and they bind the
co-ligands glycine or d-serine. NR2 subunits are approximately
twice as long as NR1 subunits.They bind glutamate, and their very
long cytosolic tails bind signal transduction molecules and link
the receptors to the postsynaptic density scaffold. Time required
to exchange waters of hydration
From Lecture 1 Time required to exchange waters of hydration Na+ ,
K+ 1 ns (~ 109/s) Na+ , K+, and Ca2+ can flow through single
channels at rates > 1000-fold greater than Mg2+ Ca2+ 5 ns (2 x
108/s) Mg2+ 10 ms (105/s) As the most charge-dense cation, Mg2+
holds its waters of hydration most tightly. Their channel opens
only when two events happen concurrently:
In NMDA receptors, the selectivity filter also serves as a Mg 2+
binding site, producing a coincidence detector. Their channel opens
only when two events happen concurrently: 1. Binding of glutamate
2. Strong postsynaptic membrane depolarization (as by an action
potential) The depolarization relieves block by Mg2+ Modified from
Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999)
Greater detail on learning & memory in a later lecture The
coincidence readout: NMDA receptors are very permeable to Ca2+
Isolating AMPA-Receptor and NMDA-Receptor Currents With Selective
Blockers #1
There is outward NMDA receptor current Nestler, Hyman, &
Malenka, Molecular Neuropharmacology Isolating AMPA-Receptor and
NMDA-Receptor Currents With Selective Blockers #2
blocks AMPA receptors There is **no** inward NMDA receptor current,
Because of Mg2+ block blocks NMDA receptors Nestler, Hyman, &
Malenka, Molecular Neuropharmacology AMPA response is faster than
NMDA response
Figure 10-6 Channels are blocked by Mg2+ at negative
potentials
Behavior of the NMDA receptor current Channels are blocked by Mg2+
at negative potentials Single channels Macroscopic I-V relations
Figure 10-5 Synthetic fluorescent dyes such as Fura-2
Detect intracellular Ca2+ transients Fura-2 Ratio Imaging From
Grynkiewicz, Poenie, and Tsien (1985) J. Biol. Chem. 260, 3440.
NMDA Receptors Mediate Synaptic Ca2+ Entry
(repeated glutamate pulses) Lisman et al.Nature Rev. Neurosci. 3:
175 (2002) In green fluorescent protein (GFP),
the fluorophore is well protected from the environment,by a can of
strands. If we render this protection sensitive to a molecule or
condition, we have a good fluorescent sensor. . Genetically encoded
fluorescent Ca2+ sensors
Circularly permuted enhanced green fluorescent protein Calmodulin
Akerboom, (30 other authors), Looger, J Neurosci Later, GCaMP6
Control of Synaptic Plasticity by NMDA Receptors
(thought to underlie some aspects of memory and learning) Greater
detail in a later lecture The central role of Ca2+ in initiation of
long-term plastic changes The Ca2+ hypothesis for control of
synaptic plasticity Measurement of cytosolic Ca2+ with fluorescent
dyes and biosensors. Control of postsynaptic Ca2+ by spike timing
Structure and behavior of the NMDA receptor Subunit composition
Gating (coincidence detection) Ion selectivity (Na+, K+, Ca2+)
Kinetics, NMDA receptors are slower than AMPA receptors
Pharmacology The NMDA receptor is also a scaffold. The postsynaptic
density LTP and LTD are triggered by Ca2+-sensitive signaling
machinery located near the mouth of the NMDA receptor. Critical
components of the postsynaptic density Biochemical pathways
mediating changes in synaptic strength Henry Lesters office
hours
Mon, Fri 1:15 2 Red Door End of Lecture 8 Friday, well return to
development for a 2nd lecture