Download Glutamate receptors

Glutamate Receptors
Primary reading:
• Hestrin S, Nicoll RA, Perkel DJ, Sah P. (1990) Analysis of excitatory
synaptic action in pyramidal cells using whole-cell recording from rat
hippocampal slices. J Physiol. 422:203-25.
Secondary readings:
• Sobolevsky AI. (2015) Structure and Gating of Tetrameric Glutamate
Receptors. J Physiol. 593:29-38.
• Traynelis SF, et al. (2010) Glutamate receptor ion channels:
structure, regulation, and function. Pharmacol Rev. 62(3):405-96.
• Granger AJ, Shi Y, Lu W, Cerpas M, Nicoll RA. (2013) LTP requires a
reserve pool of glutamate receptors independent of subunit type.
Nature. 493:495-500.
• Herring BE, Nicoll RA. (2016) Long-Term Potentiation: From CaMKII
to AMPA Receptor Trafficking. Annu Rev Physiol. 78:351-65.
• Henley JM, Wilkinson KA. (2016) Synaptic AMPA receptor
composition in development, plasticity and disease. Nat Rev
Neurosci. 17:337-50.
Outline
• History – what took so long?
• Subtypes & Pharmacology – rationale for
complexity?
• Subunit Structure – snapshot of the closed state
• Physiology & Roles in Transmission
• Specialization – alternate splicing and RNA editing
History
early evidence for excitation by glutamate
Hayashi (1954) Keio J. Medicine 3:183-192
Curtis, Phillis, and Watkins (1960) J. Physiol. 150:656-682
Krnjevic and Phillis (1963) J. Physiol. 165:274-304
Pharmacology
iGluR subtypes
NMDA
obligate heteromers GluN1 + GluN2A, B, C, or D
Ca permeable, voltage-dependent Mg block
10-20% amino acid identity to non-NMDA
non NMDA - AMPA and kainate
homomeric or heteromeric
Q / R editing site in the pore-loop
30-40% sequence identity
AMPA GluA1, 2, 3 and 4
kainate GluK1, 2, 3, 4 and 5
Rationale for complexity: integration
1.
2.
3.
4.
permeability
kinetics
modulation
trafficking
glutamate receptor pharmacology
NMDA
AMPA
kainate
agonists
glutamate
NMDA
aspartate
glutamate
AMPA
quisqualate
kainate
domoate
glutamate
kainate
domoate
(AMPA)
antagonists
APV
CNQX
GYKI53655
CNQX
permeability
Na, K, Ca
Na, K (Ca)
Na, K, (Ca)
co-agonist
glycine
channel
block
Mg
MK-801
glutamate
AMPA
kainate
NMDA
Structure
Sobolevsky et al. Nature (2009)
orientation of KcsA versus iGluR
Lee et al. (2014)
Karakas & Furukawa (2014)
AMPA Receptor Cryo-Electron Microscopy
Meyerson et al., Nature, 2014
Closed
Activated
Desensitized
Meyerson et al., Nature, 2014
Physiology
I-V relation for whole cell current
through NMDA receptors
with Mg2+
without Mg2+
Nowak et al., 1984
Voltage-dependent block of NMDA
receptor single channels by Mg2+
Nowak and Ascher, 1988
glycine is a co-agonist at NMDA receptors
Johnson and Ascher, 1987
agonist-dependent desensitization of AMPA receptors
Patneau and Mayer, 1991
kainate desensitizes kainate receptors
Huettner, 1990
I-V relations for the peak and decay phase
Hestrin et al., 1990
APV blocks the slow component of transmission
Hestrin et al., 1990
CNQX blocks the fast component
Hestrin et al., 1990
voltage-dependent block by Mg2+
Hestrin et al., 1990
Why is the NMDA receptor-mediated component slow?
Lester et al., 1990
brief pulses of glutamate elicit prolonged bursts
Lester et al., 1990
Specialization
Alternate splicing can alter gating,
modulation and trafficking
• Flip/flop 38 amino acid modules in the S2
loop that control gating kinetics
• Cytoplasmic sites for post-translational
modification and binding to cytosolic
proteins depend on C-terminal splicing
splicing
and
editing
Flip/flop splicing alters desensitization kinetics
Mosbacher et al., 1994
Sommer et al., 1990
C-tail splicing alters modulation and trafficking
Bredt and Nicoll, 2003
Chung et al., 2000
Bredt and Nicoll, 2003
RNA Editing can alter permeation and gating
• Q/R site in GluA2 and GluK1 & 2 controls
permeation, polyamine block and lipid
modulation
• R/G site in GluA2, 3 & 4 just before flip/flop
splice module affects kinetics of
desensitization
adenosine deaminase
Met Gln Gln
AUG CAG CAA
Met Arg Gln
AUG CIG CAA
intronic hairpins define the editing site
Seeburg et al., 1998
Q/R site RNA editing regulates permeation
Q/R site RNA editing determines
polyamine block and fatty acid modulation
GluK2(Q)
Wilding et al., 2005; 2008
GluK2(R)
differences in EPSC time course
Trussell, 1999
summary
• Ionotropic glutamate receptors mediate fast excitatory
transmission throughout the CNS
• Structural diversity allows for control of permeation,
kinetics, modulation and trafficking
• AMPA and NMDA receptors are the major postsynaptic
receptors; kainate receptors can be pre- or postsynaptic
• High calcium permeability and voltage-dependent block by
magnesium underlie the role of NMDA receptors in
controlling synaptic plasticity
• Insertion and removal of AMPA receptors is a major
determinant of synaptic strength