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Desensitization of ionotropic glutamate receptors (GluRs), specifically the AMPA receptor subtype, shapes the postsynaptic response at certain synapses in the brain. All known mechanisms that alter desensitization, either pharmacological or mutational, are associated with the ligand-binding domain. Here we report that substitution of a conserved positively charged arginine (R) with a negatively charged glutamate in the linker between the pore-forming M3 segment and the S2 lobe, a region outside the ligand-binding domain, blocks desensitization in homomeric AMPA receptors composed of GluR-B(i) subunits. A charge-reversing substitution of a glutamate adjacent to this conserved R enhanced desensitization, consistent with these effects attributable to electrostatics. Homologous substitutions of the conserved R in GluR-B(o), GluR-A(i) and the kainate receptor GluR-6 subunits produced comparable but less visible effects on desensitization. Subunit specificity was also apparent for accessibility of substituted cysteines in the M3-S2 linker, suggesting that this part of the channel is not structurally identical in different GluRs. Additionally, reactivity with a sulfhydryl-specific reagent was state dependent, suggesting that the conformations of the nonconducting closed and desensitized states are different at the level of the M3-S2 linker. Our results therefore represent the first identification of elements outside the ligand-binding domain affecting desensitization in non-NMDA receptor channels and suggest that electrostatic interactions involving charged residues in the M3-S2 linker influence channel gating in a subunit- and subtype-specific manner.
Armstrong,
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.
2000, Pubmed
Armstrong,
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.
2000,
Pubmed Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998,
Pubmed Banke,
Identification of amino acid residues in GluR1 responsible for ligand binding and desensitization.
2001,
Pubmed
,
Xenbase Beck,
NMDAR channel segments forming the extracellular vestibule inferred from the accessibility of substituted cysteines.
1999,
Pubmed
,
Xenbase Bowie,
Activity-dependent modulation of glutamate receptors by polyamines.
1998,
Pubmed Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed Glavinovíc,
Monte Carlo simulation of spontaneous miniature excitatory postsynaptic currents in rat hippocampal synapse in the presence and absence of desensitization.
1998,
Pubmed Jatzke,
Extracellular vestibule determinants of Ca2+ influx in Ca2+-permeable AMPA receptor channels.
2003,
Pubmed Jones,
The NMDA receptor M3 segment is a conserved transduction element coupling ligand binding to channel opening.
2002,
Pubmed
,
Xenbase Jones,
The impact of receptor desensitization on fast synaptic transmission.
1996,
Pubmed Karlin,
Substituted-cysteine accessibility method.
1998,
Pubmed Kash,
Coupling of agonist binding to channel gating in the GABA(A) receptor.
2003,
Pubmed Kohda,
Mutation of a glutamate receptor motif reveals its role in gating and delta2 receptor channel properties.
2000,
Pubmed Köhler,
Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing.
1993,
Pubmed Koike,
Regulation of kinetic properties of GluR2 AMPA receptor channels by alternative splicing.
2000,
Pubmed
,
Xenbase Kuner,
Channel-lining residues of the AMPA receptor M2 segment: structural environment of the Q/R site and identification of the selectivity filter.
2001,
Pubmed
,
Xenbase Kuner,
A common architecture for K+ channels and ionotropic glutamate receptors?
2003,
Pubmed Kuner,
Structure of the NMDA receptor channel M2 segment inferred from the accessibility of substituted cysteines.
1996,
Pubmed
,
Xenbase Larsson,
A conserved glutamate is important for slow inactivation in K+ channels.
2000,
Pubmed
,
Xenbase Mansour,
Heteromeric AMPA receptors assemble with a preferred subunit stoichiometry and spatial arrangement.
2001,
Pubmed Mosbacher,
A molecular determinant for submillisecond desensitization in glutamate receptors.
1994,
Pubmed
,
Xenbase Partin,
Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A.
1993,
Pubmed
,
Xenbase Partin,
Domain interactions regulating ampa receptor desensitization.
2001,
Pubmed
,
Xenbase Partin,
AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate.
1996,
Pubmed Partin,
Structural determinants of allosteric regulation in alternatively spliced AMPA receptors.
1995,
Pubmed
,
Xenbase Partin,
Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants.
1994,
Pubmed
,
Xenbase Robert,
How AMPA receptor desensitization depends on receptor occupancy.
2003,
Pubmed Robert,
Subunit interactions and AMPA receptor desensitization.
2001,
Pubmed Seeburg,
The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels.
1993,
Pubmed Sobolevsky,
Molecular rearrangements of the extracellular vestibule in NMDAR channels during gating.
2002,
Pubmed
,
Xenbase Sobolevsky,
Different gating mechanisms in glutamate receptor and K+ channels.
2003,
Pubmed
,
Xenbase Sobolevsky,
The outer pore of the glutamate receptor channel has 2-fold rotational symmetry.
2004,
Pubmed
,
Xenbase Stern-Bach,
A point mutation in the glutamate binding site blocks desensitization of AMPA receptors.
1998,
Pubmed Sun,
Mechanism of glutamate receptor desensitization.
2002,
Pubmed Watanabe,
DRPEER: a motif in the extracellular vestibule conferring high Ca2+ flux rates in NMDA receptor channels.
2002,
Pubmed
,
Xenbase Wollmuth,
Differential contribution of the NR1- and NR2A-subunits to the selectivity filter of recombinant NMDA receptor channels.
1996,
Pubmed
,
Xenbase
